Method, Device and System for Modulating an Activity of Brown Adipose Tissue in a Vertebrate Subject

ABSTRACT

Devices, systems, and methods are disclosed herein for treatment of a disease, disorder, or condition in a vertebrate subject. A device is provided that includes one or more cooling elements configured to be applied to one or more tissues of a vertebrate subject to modulate at least one activity of brown adipose tissue of the vertebrate subject, and a programmable controller configured to provide instructions to the one or more cooling elements in response to information regarding one or more physiological conditions of the vertebrate subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is related to and claims the benefit of theearliest available effective filing date(s) from the following listedapplication(s) (the “Related Applications”) (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 USC §119(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Related Application(s)). All subject matter ofthe Related Applications and of any and all parent, grandparent,great-grandparent, etc. applications of the Related Applications isincorporated herein by reference to the extent such subject matter isnot inconsistent herewith.

RELATED APPLICATIONS

-   -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of United        States patent application No. To be Assigned, entitled METHOD,        DEVICE AND SYSTEM FOR MODULATING AN ACTIVITY OF BROWN ADIPOSE        TISSUE IN A VERTEBRATE SUBJECT, naming Edward S. Boyden,        Roderick A. Hyde, Muriel Y. Ishikawa, Edward K. Y. Jung, Eric C.        Leuthardt, Stephen L. Malaska, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 9 May 2011, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.    -   For purposes of the USPTO extra-statutory requirements, the        present application constitutes a continuation-in-part of United        States patent application No. To be Assigned, entitled METHOD,        DEVICE AND SYSTEM FOR MODULATING AN ACTIVITY OF BROWN ADIPOSE        TISSUE IN A VERTEBRATE SUBJECT, naming Edward S. Boyden,        Roderick A. Hyde, Muriel Y. Ishikawa, Edward K Y. Jung, Eric C.        Leuthardt, Stephen L. Malaska, Elizabeth A. Sweeney and        Lowell L. Wood, Jr. as inventors, filed 9 May 2011, which is        currently co-pending, or is an application of which a currently        co-pending application is entitled to the benefit of the filing        date.

The United States Patent Office (USPTO) has published a notice to theeffect that the USPTO's computer programs require that patent applicantsreference both a serial number and indicate whether an application is acontinuation, continuation-in-part, or divisional of a parentapplication. Stephen G. Kunin, Benefit of Prior-Filed Application, USPTOOfficial Gazette Mar. 18, 2003. The present Applicant Entity(hereinafter “Applicant”) has provided above a specific reference to theapplication(s) from which priority is being claimed as recited bystatute. Applicant understands that the statute is unambiguous in itsspecific reference language and does not require either a serial numberor any characterization, such as “continuation” or“continuation-in-part,” for claiming priority to U.S. patentapplications. Notwithstanding the foregoing, Applicant understands thatthe USPTO's computer programs have certain data entry requirements, andhence Applicant has provided designation(s) of a relationship betweenthe present application and its parent application(s) as set forthabove, but expressly points out that such designation(s) are not to beconstrued in any way as any type of commentary and/or admission as towhether or not the present application contains any new matter inaddition to the matter of its parent application(s).

SUMMARY

A device is disclosed herein that can be used in a method for modulatingmetabolic activity of a brown adipose tissue in a vertebrate subject.The device can be used in a method for inducing weight loss in avertebrate subject or in a method for treating a disorder, e.g., ametabolic disorder, diabetes, obesity, metabolic syndrome, ordyslipidemia, in a vertebrate subject. The device includes one or morecooling elements configured to be applied to one or more tissues of avertebrate subject to modulate at least one activity of brown adiposetissue of the vertebrate subject, and a programmable controllerconfigured to provide instructions to the one or more cooling elementsin response to information regarding one or more physiologicalconditions of the vertebrate subject. The device can further compriseone or more sensors operably connected to the programmable controller,wherein the programmable controller is configured to provideinstructions to the one or more cooling elements in response toinformation from the one or more sensors regarding one or morephysiological conditions of the vertebrate subject.

A device is disclosed herein that includes one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectto modulate at least one activity of brown adipose tissue of thevertebrate subject, and a programmable controller configured to provideinstructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. The device can further include one or more sensorsoperably connected to the programmable controller, wherein theprogrammable controller is configured to provide instructions to the oneor more cooling elements in response to information from the one or moresensors regarding one or more physiological conditions of the vertebratesubject. The programmable controller can be configured to receiveinformation regarding the one or more physiological conditions from theone or more sensors. The device can further include a digital processingunit operably connected to the programmable controller, the digitalprocessing unit configured to receive information from at least one of asensor, a timekeeping device, a user interface, and an outside operatingsource and process the information into at least one resultinginstruction and providing the at least one resulting instruction to theprogrammable controller. The information regarding the one or morephysiological conditions can include information regarding one or moreanalytes in the vertebrate subject. The information regarding the one ormore physiological conditions can include a plasma level of one or moreanalytes in the vertebrate subject. The information regarding the one ormore physiological conditions can include, but is not limited to, alevel of one or more of a metabolic analyte, a sugar, a lipoprotein, ora fatty acid in the vertebrate subject. The information regarding theone or more physiological conditions can include information regardingthe at least one activity of the brown adipose tissue.

The device can further include an outside operating source operablyconnected to the programmable controller, wherein the programmablecontroller in communication with the outside operating source isconfigured to provide instructions to the one or more cooling elementsin response to information from the outside operating source regardingthe one or more physiological conditions of the vertebrate subject. Theoutside operating source can include, but is not limited to, a computingdevice or a human operator. The programmable controller can beconfigured to accept or send information from or to one or more of atimekeeping device or a user interface. The timekeeping device can beinternal to the programmable controller. The programmable controller canbe configured to accept user input. The user input can include, but isnot limited to, time input, time of day, period of time, start time,stop time, or length of time. The information regarding thephysiological condition can include information relating to one or moreof calories ingested by the vertebrate subject or food ingested by thevertebrate subject. The device can further include at least one ofcircuitry and data storage. The device can include programming. Thedevice can include programming designed to induce weight loss. Thedevice can include programming designed to treat a disorder.

In the device, modulating the at least one activity of the brown adiposetissue can include increasing metabolic activity of brown adipose tissueor increasing proliferation of brown adipose tissue in the vertebratesubject. Modulating the at least one activity of the brown adiposetissue can include inducing non-shivering thermogenesis in the brownadipose tissue. The one or more tissues can include thermoresponsivetissue of the vertebrate subject. The one or more tissues can includenervous tissue of the vertebrate subject. The one or more tissues caninclude cutaneous tissue of the vertebrate subject. The one or moretissues can include brown adipose tissue. The one or more tissues caninclude tissue in a core of the body of the vertebrate subject. The oneor more tissues can include one or more blood vessels or lymph vessels.

The one or more cooling elements can include one or more electricalcooling elements. The one or more cooling elements can include one ormore Peltier cooling elements. The one or more cooling elements caninclude one or more chemical cooling elements. The one or more coolingelements can be configured to attain a tissue temperature fromapproximately 4° C. to approximately 36° C. The one or more coolingelements can be configured to attain a tissue temperature fromapproximately 12° C. to approximately 20° C. The one or more coolingelements can be configured to attain a tissue temperature fromapproximately 24° C. to approximately 32° C. The one or more coolingelements can be configured to attain a tissue temperature approximately16° C. or lower. The device can be configured to be incorporated withclothing, bedding, furniture, or upholstery. The device can furtherinclude a power source configured to power the device. The power sourcecan include, but is not limited to, stored power, a battery, a fuelcell, or beamed power.

The device can further include a neurostimulator configured to beapplied to the one or more tissues. The device can further include aneurostimulator configured to be applied to one or more second tissuesof the vertebrate subject. The one or more second tissues can includenerve tissue. The neurostimulator can include at least one of electricneurostimulator, magnetic neurostimulator, ultrasonic neurostimulator,or microwave neurostimulator. The device can further include anapplicator configured to deliver a therapeutic medicament.

A method for modulating an activity of brown adipose tissue of avertebrate subject is disclosed herein that includes: applying coolingto one or more tissues of the vertebrate subject with one or morecooling elements, wherein the one or more cooling elements areconfigured to lower the temperature of the one or more tissues andthereby modulate at least one activity of the brown adipose tissue ofthe vertebrate subject, and controlling the one or more cooling elementswith a programmable controller configured to provide instructions to theone or more cooling elements in response to information regarding one ormore physiological conditions of the vertebrate subject. The method canfurther include sensing with one or more sensors the informationregarding the one or more physiological conditions and communicating theinformation from the one or more sensors to the programmable controller.The method can further include sensing with one or more sensors theinformation regarding the one or more physiological conditions andcommunicating the information from the one or more sensors to a digitalprocessing unit, processing the information with the digital processingunit into at least one resulting instruction, and providing by thedigital processing unit the at least one resulting instruction to theprogrammable controller.

In the method, processing the information can include comparing theinformation regarding the one or more physiological conditions toinformation of a standard value or preprogrammed value. The informationregarding the one or more physiological conditions can include a plasmalevel of one or more metabolic analytes in the vertebrate subject. Theinformation regarding the one or more physiological conditions caninclude a sugar levels or fatty acid level in the vertebrate subject.The method can further include providing information from at least oneof a sensor, a timekeeping device, a user interface, and an outsideoperating source to a digital processing unit, processing theinformation with the digital processing unit into at least one resultinginstruction, and providing by the digital processing unit the at leastone resulting instruction to the programmable controller. The outsideoperating source can include, but is not limited to, a computing device,a user input device, the timekeeping device, a sensing device, or ahuman operator. The timekeeping device can be internal to theprogrammable controller. In the method, controlling the one or morecooling elements with the programmable controller can includeprogramming the programmable controller. Programming the programmablecontroller can occur by a user or by a digital processing unit. In themethod, controlling the one or more cooling elements with theprogrammable controller includes programming the programmable controllerto induce weight loss. In the method, controlling the one or morecooling elements with the programmable controller includes programmingthe programmable controller to treat a disorder.

The method can further include inputting information into the device bya user. The user input information can include information relating toone or more of calories ingested by the vertebrate subject or foodingested by the vertebrate subject. The user input information caninclude, but is not limited to, time input, time of day, period of time,start time, stop time, or length of time. The information regarding theone or more physiological conditions can include information relating toone or more of calories ingested by the vertebrate subject or foodingested by the vertebrate subject. In the method, modulating the atleast one activity of the brown adipose tissue can include increasingmetabolic activity, or increasing proliferation of brown adipose tissuein the vertebrate subject. In the method, modulating the at least oneactivity of the brown adipose tissue can include inducing non-shiveringthermogenesis in the brown adipose tissue.

The one or more tissues can include thermoresponsive tissue of thevertebrate subject. The one or more tissues can include nervous tissueof the vertebrate subject. The one or more tissues can include cutaneoustissue of the vertebrate subject. The one or more tissues can includebrown adipose tissue. The one or more tissues can include tissue in acore of the body of the vertebrate subject. The one or more tissues caninclude digestive tissue. The one or more tissues can include one ormore blood vessels or lymph vessels.

The one or more cooling elements can be configured to cool by electricalcooling activity. The one or more cooling elements can be configured tocool by Peltier cooling activity. The one or more cooling elements canbe configured to cool by chemical cooling activity. The method canfurther include cooling the tissue with the one or more cooling elementsto a tissue temperature from approximately 4° C. to approximately 36° C.The method can further include cooling the tissue with the one or morecooling elements to a tissue temperature from approximately 12° C. toapproximately 20° C. The method can further include cooling the tissuewith the one or more cooling elements to attain a tissue temperaturefrom approximately 24° C. to approximately 32° C. The method can furtherinclude cooling the tissue with the one or more cooling elements to atissue temperature approximately 16° C. or lower. The one or morecooling elements can be incorporated in into clothing, bedding,furniture, or upholstery. The method can further include powering thedevice with a power source. The power source can include, but is notlimited to, stored power, a battery, or a fuel cell.

The vertebrate subject can be undergoing further treatment for at leastone of weight loss, diabetes, obesity, metabolic syndrome, ordyslipidemia. The method can further include providing one or moremedicaments for treatment of weight loss, metabolic disorder, diabetes,obesity, metabolic syndrome, or dyslipidemia. The one or moremedicaments can include one or more of β-adrenergic receptor agonist,NPY antagonist, leptin, UCP activating agent, thyroxine, serotoninreuptake inhibitor, MCH antagonist, GLP-1 agonist, 5-HT2C agonist,5-HT2A agonist, galanin antagonist, CRF agonist, urocortin agonist,melanocortin agonist or enterostatin agonist.

The method can further include applying a neurostimulator to the one ormore tissues. The method can further include applying a neurostimulatorto one or more second tissues of the vertebrate subject. The one or moresecond tissues can include nerve tissue. In the method, applying theneurostimulator can include applying at least one of electricneurostimulator, magnetic neurostimulator, ultrasonic neurostimulator,or microwave neurostimulator.

A method for inducing weight loss in a vertebrate subject is disclosedherein that includes: applying cooling to one or more tissues of thevertebrate subject with one or more cooling elements, wherein the one ormore cooling elements are configured to lower the temperature of the oneor more tissues and thereby modulate at least one activity of brownadipose tissue of the vertebrate subject, and controlling the one ormore cooling elements with a programmable controller configured toprovide instructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. The method can further include sensing with one ormore sensors the information regarding the one or more physiologicalconditions and communicating the information from the one or moresensors to the programmable controller. The method can further includesensing with one or more sensors the information regarding the one ormore physiological conditions and communicating the information from theone or more sensors to a digital processing unit, processing theinformation with the digital processing unit into at least one resultinginstruction, and providing by the digital processing unit the at leastone resulting instruction to the programmable controller.

The method can further include providing information from at least oneof a sensor, a timekeeping device, a user interface, and an outsideoperating source to a digital processing unit, processing theinformation with the digital processing unit into at least one resultinginstruction, and providing by the digital processing unit the at leastone resulting instruction to the programmable controller. The outsideoperating source can include, but is not limited to, a computing device,a user input device, the timekeeping device, a sensing device, or ahuman operator. In the method, processing the information can includecomparing the information regarding the one or more physiologicalconditions to information of a standard value or preprogrammed value.The information regarding the one or more physiological conditions caninclude a plasma level of one or more metabolic analytes in thevertebrate subject. The information regarding the one or morephysiological conditions can include, but is not limited to, a sugarlevel or a fatty acid level in the vertebrate subject. The method canfurther include inputting information into the device by a user. Theuser input information can include information relating to one or moreof calories ingested by the vertebrate subject or food ingested by thevertebrate subject. The user input information can include, but is notlimited to, time input, time of day, period of time, start time, stoptime, or length of time. In the method, modulating the at least oneactivity of the brown adipose tissue can include increasing metabolicactivity, or increasing proliferation of brown adipose tissue in thevertebrate subject. In the method, modulating the at least one activityof the brown adipose tissue can include inducing non-shiveringthermogenesis in the brown adipose tissue.

A method for treating a disorder in a vertebrate subject is disclosedherein that includes applying cooling to one or more tissues of thevertebrate subject with one or more cooling elements, wherein the one ormore cooling elements are configured to lower the temperature of the oneor more tissues and thereby modulate at least one activity of brownadipose tissue of the vertebrate subject, and controlling the one ormore cooling elements with a programmable controller configured toprovide instructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject.

The method can further include sensing with one or more sensorsinformation regarding the one or more physiological conditions andcommunicating the information from the one or more sensors to theprogrammable controller. The method can further include sensing with oneor more sensors information regarding the one or more physiologicalconditions and communicating the information from the one or moresensors to a digital processing unit, processing the information withthe digital processing unit into at least one resulting instruction, andproviding by the digital processing unit the at least one resultinginstruction to the programmable controller. The outside operating sourcecan include a computing device, a user input device, the timekeepingdevice, a sensing device, or a human operator. In the method, processingthe information can include comparing the information regarding the oneor more physiological conditions to information of a standard value orpreprogrammed value. The method of can further include providinginformation from at least one of a sensor, a timekeeping device, a userinterface, and an outside operating source to a digital processing unit,processing the information with the digital processing unit into atleast one resulting instruction, and providing by the digital processingunit the at least one resulting instruction to the programmablecontroller.

The information regarding the one or more physiological conditions caninclude a plasma level of one or more metabolic analytes in thevertebrate subject. The information regarding the one or morephysiological conditions can include a sugar level or a fatty acid levelin the vertebrate subject. The method can further include inputtinginformation into the device by a user. The user input information caninclude information relating to one or more of calories ingested by thevertebrate subject or food ingested by the vertebrate subject. The userinput information can include, but is not limited to, time input, timeof day, period of time, start time, stop time, or length of time. In themethod, modulating the at least one activity of the brown adipose tissueincludes increasing metabolic activity, or increasing proliferation ofbrown adipose tissue in the vertebrate subject. In the method,modulating the at least one activity of the brown adipose tissueincludes inducing non-shivering thermogenesis in the brown adiposetissue.

A method for treating a metabolic disorder in a vertebrate subject isdisclosed herein that includes applying cooling to one or more tissuesof the vertebrate subject with one or more cooling elements, wherein theone or more cooling elements are configured to lower the temperature ofthe one or more tissues and thereby modulate at least one activity ofbrown adipose tissue of the vertebrate subject, and controlling the oneor more cooling elements with a programmable controller configured toprovide instructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject.

The method can further include sensing with one or more sensors theinformation regarding the one or more physiological conditions andcommunicating the information from the one or more sensors to theprogrammable controller. The method can further include sensing with oneor more sensors the information regarding the one or more physiologicalconditions and communicating the information from the one or moresensors to a digital processing unit, processing the information withthe digital processing unit into at least one resulting instruction, andproviding by the digital processing unit the at least one resultinginstruction to the programmable controller. The method can furtherinclude providing information from at least one of a sensor, atimekeeping device, a user interface, and an outside operating source toa digital processing unit, processing the information with the digitalprocessing unit into at least one resulting instruction, and providingby the digital processing unit the at least one resulting instruction tothe programmable controller.

A system is disclosed herein that includes a non-transitorysignal-bearing medium configured for use in a computing deviceincluding, one or more instructions for receiving data including datafor applying cooling to one or more tissues of a vertebrate subject withone or more cooling elements of a treatment device, wherein the one ormore cooling elements are configured to modulate at least one activityof brown adipose tissue of the vertebrate subject; and one or moreinstructions for receiving data including data for controlling the oneor more cooling elements with a programmable controller configured toprovide instructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. The system can further include one or moreinstructions for receiving data including data for processing theinformation regarding the one or more physiological conditions from oneor more sensors operably connected to the programmable controller, andproviding the instructions to the one or more cooling elements inresponse to the processed information from the one or more sensors tothe programmable controller. The system can further include one or moreinstructions for receiving data including data for processing theinformation regarding the one or more physiological conditions from anoutside operating source. The outside operating source can include, butis not limited to, a computing device or a human operator. In thesystem, processing the information includes comparing the informationregarding the one or more physiological conditions to information of astandard value or preprogrammed value.

The information regarding the one or more physiological conditions caninclude a plasma level of one or more metabolic analytes in thevertebrate subject. The information regarding the one or morephysiological conditions can include a sugar level or a fatty acid levelin the vertebrate subject. The system can further include providinginformation from at least one of a sensor, a timekeeping device, a userinterface, and an outside operating source to a digital processing unit,processing the information into at least one resulting instruction, andproviding the at least one resulting instruction to the programmablecontroller. The outside operating source can include, but is not limitedto, a computing device, a user input device, the timekeeping device, ora human operator. The timekeeping device can be internal to theprogrammable controller. In the system, controlling the one or morecooling elements with the programmable controller can includeprogramming the programmable controller. In the system, programming theprogrammable controller can occur by a user or by a digital processingunit. The user input can include information relating to one or more ofcalories ingested by the vertebrate subject or food ingested by thevertebrate subject. The user input can include, but is not limited to,time input, time of day, period of time, start time, stop time, orlength of time.

In the system, modulating the at least one activity of the brown adiposetissue can include increasing metabolic activity, or increasingproliferation of brown adipose tissue in the vertebrate subject. In thesystem, modulating the at least one activity of the brown adipose tissuecan include inducing non-shivering thermogenesis in the brown adiposetissue. In the system, controlling the one or more cooling elements withthe programmable controller can include programming the programmablecontroller to induce weight loss. In the system, controlling the one ormore cooling elements with the programmable controller can includeprogramming the programmable controller to treat a disorder.

The system can further include one or more instructions for receivingdata including data for powering the device with a power source. Thesystem can further include one or more instructions for receiving dataincluding data for providing one or more medicaments for treatment ofweight loss, metabolic disorder, diabetes, obesity, metabolic syndrome,or dyslipidemia. The system can further include one or more instructionsfor receiving data including data for applying a neurostimulator to theone or more tissues. The system can further include one or moreinstructions for receiving data including data for applying aneurostimulator to one or more second tissues of the vertebrate subject.The system can further include one or more instructions for receivingdata including data from at least one user interface. The system canfurther include one or more instructions for receiving data includingdata from at least one signal emitter. The system can further includeone or more instructions for receiving data including data from digitalmemory.

A system is disclosed herein that includes one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectto modulate at least one activity of brown adipose tissue of thevertebrate subject, and a programmable controller configured to transmitinstructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. The system can further include one or more sensorsoperably connected to the programmable controller, wherein theprogrammable controller is configured to provide instructions to the oneor more cooling elements in response to information from the one or moresensors, wherein the one or more sensors are configured to sense one ormore physiological conditions of the vertebrate subject. The system canfurther include at least one user interface. The system can furtherinclude digital memory.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A, 1B and 1C are a schematic of a diagrammatic view of an aspectof an embodiment of a device.

FIG. 2 is a schematic of a diagrammatic view of an aspect of anembodiment of a device.

FIG. 3 is a schematic of a diagrammatic view of an aspect of anembodiment of a device.

FIG. 4 is a schematic of a diagrammatic view of an aspect of anembodiment of a device.

FIG. 5 is a schematic of a diagrammatic view of an aspect of anembodiment of a device.

FIG. 6 is a schematic of a diagrammatic view of an aspect of anembodiment of a device.

FIG. 7 is a schematic of a diagrammatic view of an aspect of anembodiment of a method for treating a metabolic disorder in a vertebratesubject.

FIG. 8 is a schematic of a diagrammatic view of an aspect of anembodiment of a method for treating a metabolic disorder in a vertebratesubject.

FIG. 9 is a schematic of a diagrammatic view of an aspect of anembodiment of a method for treating a metabolic disorder in a vertebratesubject.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

This document uses formal outline headings for clarity of presentation.However, it is to be understood that the outline headings are forpresentation purposes, and that different types of subject matter may bediscussed throughout the application (e.g., method(s) may be describedunder composition heading(s) and/or kit headings, and/or descriptions ofsingle topics may span two or more topic headings). Hence, the use ofthe formal outline headings is not intended to be in any way limiting.

A device is disclosed herein that can be used in a method for modulatingan activity of brown adipose tissue in a vertebrate subject. The devicecan be used in a method for inducing weight loss in a vertebrate subjector in a method for treating a disorder, e.g., a metabolic disorder,diabetes, obesity, metabolic syndrome, or dyslipidemia, in a vertebratesubject. The device includes one or more cooling elements configured tobe applied to one or more tissues of a vertebrate subject to modulate atleast one activity of brown adipose tissue of the vertebrate subject,and a programmable controller configured to provide instructions to theone or more cooling elements in response to information regarding one ormore physiological conditions of the vertebrate subject. The device canfurther comprise one or more sensors operably connected to theprogrammable controller, wherein the programmable controller isconfigured to provide instructions to the one or more cooling elementsin response to information from the one or more sensors regarding one ormore physiological conditions of the vertebrate subject.

A method for modulating an activity of brown adipose tissue of avertebrate subject is disclosed herein that includes applying cooling toone or more tissues of the vertebrate subject with one or more coolingelements, wherein the one or more cooling elements are configured tolower the temperature of the one or more tissues and thereby modulate atleast one activity of the brown adipose tissue of the vertebratesubject, controlling the one or more cooling elements with aprogrammable controller configured to provide instructions to the one ormore cooling elements in response to information regarding one or morephysiological conditions of the vertebrate subject.

A device is disclosed herein that includes one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectto modulate at least one activity of brown adipose tissue of thevertebrate subject, wherein at least a portion of the one or morecooling elements is configured to be implantable, and a programmablecontroller configured to provide instructions to the one or more coolingelements in response to information regarding one or more physiologicalconditions of the vertebrate subject. The device can further include oneor more sensors operably connected to the programmable controller,wherein the programmable controller is configured to provideinstructions to the one or more cooling elements in response toinformation from the one or more sensors.

A method for modulating an activity of brown adipose tissue in avertebrate subject is disclosed herein that includes applying cooling toone or more tissues of the vertebrate subject with one or more coolingelements, wherein the one or more cooling elements are configured tolower the temperature of the one or more tissues and thereby modulate atleast one activity of the brown adipose tissue of the vertebratesubject, wherein at least a portion of the one or more cooling elementsis configured to be implantable, and controlling the one or more coolingelements with a programmable controller configured to provideinstructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject.

A device is disclosed herein that includes one or more passive coolingelements configured to be applied to one or more tissues of a vertebratesubject to modulate at least one activity of brown adipose tissue of thevertebrate subject, wherein at least a portion of the one or morepassive cooling elements is configured to be implantable, and whereinthe one or more passive cooling elements includes a first portionconfigured to be in association with the one or more tissues to becooled, and a second portion configured to be placed in association withone or more tissues adjacent to an external epidermal tissue of thevertebrate subject. The second portion of the one or more passivecooling elements can further include one or more branches configured tobe placed in association with the one or more tissues adjacent to theexternal epidermal tissue of the vertebrate subject.

A method for modulating an activity of brown adipose tissue in avertebrate subject is disclosed herein that includes applying cooling toone or more tissues of the vertebrate subject with one or more passivecooling elements, wherein the one or more passive cooling elements areconfigured to lower the temperature of the one or more tissues andthereby modulate at least one activity of the brown adipose tissue ofthe vertebrate subject, wherein at least a portion of the one or morepassive cooling elements is configured to be implantable, and whereinthe one or more passive cooling elements includes a first portionconfigured to be in association with the one or more tissues to becooled, and a second portion configured to be placed in association withone or more tissues adjacent to an external epidermal tissue of thevertebrate subject. The second portion of the one or more passivecooling elements can further include one or more branches configured tobe placed in association with the one or more tissues adjacent to theexternal epidermal tissue of the vertebrate subject.

The device described herein includes one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectto modulate at least one activity of brown adipose tissue, for exampleto enhance at least one activity of brown adipose tissue, for example topromote non-shivering thermogenesis in brown adipocytes of thevertebrate subject. The device can be used in a method for modulating anactivity, e.g., a metabolic activity of brown adipose tissue of avertebrate subject. The device can be used in a method for inducingweight loss in a vertebrate subject. The device can be used in a methodfor treating one or more disorders in a vertebrate subject including,but not limited to, overweightedness, obesity, a metabolic disorder,diabetes, dyslipidemia, and metabolic syndrome.

The device includes one or more cooling elements to be applied to one ormore tissues of the subject, for example one or more tissues thatinclude a thermoresponsive tissue, e.g., tissues having cold-sensitivethermoreceptors or sensory neurons. The one or more cooling elements caninclude, but are not limited to, one or more electrical coolingelements, one or more Peltier cooling elements, one or more chemicalcooling elements. The one or more cooling elements can further includeone or more heat pumps. The one or more cooling elements can include oneor more nanoparticles, microparticles, paramagnetic particles, magneticparticles, chemical core particles, or one or more endothermicbiodegradable particles. The one or more cooling elements can includeone or more systems for passive cooling or active cooling using a heatsink or heat pipes.

The one or more cooling elements of the device can be applied to one ormore tissues of a vertebrate subject. The one or more tissues caninclude one or more thermoresponsive tissue. The one or more tissues caninclude, but are not limited to, nervous tissue, cutaneous tissue, coretissue, brown adipose tissue, blood vessels, or combinations thereof.Cutaneous tissue can include, but is not limited to, epidermal tissue,dermal tissue, or highly vascularized dermal tissue. Core tissue caninclude, but is not limited to, any tissue internal to the body e.g., anorgan in the viscera, or a deep vein, such as a great vein or apulmonary vein. Blood vessels can be located in the core tissue, e.g., adeep vein, or in the cutaneous tissue of the vertebrate subject, and caninclude large blood vessels, e.g., superficial veins, such as saphenousvein.

The device described herein includes a programmable controllerconfigured to provide instructions to the one or more cooling elementsfor cooling one or more tissues in a vertebrate subject. The device canfurther include a neurostimulator configured to be applied to the one ormore tissues or to one or more other tissues in combination with the oneor more cooling elements. The neurostimulator can include but is notlimited to an electric neurostimulator, optical neurostimulator, amagnetic neurostimulator, an ultrasonic neurostimulator, or a microwaveneurostimulator. In an aspect, the device can include one or moreneurostimulators configured to stimulate nerves involved in inducingthermogenesis in brown adipose tissue. The neurostimulator can be in thesame unit as the device that includes the one or more cooling elements,or the neurostimulator can be in a separate unit from the device thatincludes the one or more cooling elements. The neurostimulator can beapplied to the one or more tissues to which the cooling elements havebeen applied. Alternatively or in addition, the neurostimulator can beapplied to one or more second tissues of the vertebrate subject otherthan the one or more tissues. The neurostimulator can be applied to atissue that includes a nervous tissue or to an innervated tissue.

The device can include a programmable controller operably connected tothe one or more cooling elements, wherein the programmable controller isconfigured to provide instructions to the one or more cooling elementsin response to information regarding one or more physiologicalconditions of the vertebrate subject. The device can further include oneor more sensors operably connected to the programmable controller,wherein the programmable controller is configured to provideinstructions to the one or more cooling elements in response toinformation from the one or more sensors regarding one or morephysiological conditions of the vertebrate subject. The one or morephysiological conditions can include a plasma level and/or localizedtissue level of one or more analytes in the subject, which may be one ormore metabolic analyte. In an aspect, the one or more analytes caninclude an analyte associated with a metabolic disorder. The one or moremetabolic analyte indicative of a metabolic disorder include, but arenot limited to, blood glucose, free fatty acids, triglycerides, insulin,glucagon, pro-inflammatory molecules, cholesterol, low densitylipoprotein (LDL), and high-density lipoprotein (HDL), blood pressure,or heart rate. The one or more sensors are configured to provide data tothe programmable controller regarding the plasma and/or tissue levels ofmetabolic analytes associated with a disorder, e.g., a metabolicdisorder, diabetes, obesity, metabolic syndrome, or dyslipidemia, in thevertebrate subject.

Thermogenesis in Brown Adipose Tissue

Adipose tissue in mammals and some non-mammal vertebrates is composed ofat least two distinct forms of adipose termed white adipose and brownadipose that differ significantly in both structure and function, asreviewed by Saely, et al., “Brown versus White Adipose Tissue: AMini-Review,” Gerontology, Karger A G, Basel, Dec. 7, 2010. Whiteadipose tissue is the primary site of energy storage in the form of fat,and excess accumulation of fat in subcutaneous and visceral whiteadipose tissue depots leads to weight gain and obesity. White adiposetissue is also involved in releasing hormones and cytokines thatmodulate whole-body metabolism and insulin resistance. White adipocytes,the primary cellular component of white adipose tissue, arecharacterized by a single large lipid droplet. In contrast, brownadipose tissue is important for both basal and inducible energyexpenditure in the form of thermogenesis (i.e., heat production)mediated by the activity of uncoupling protein 1 (UCP-1), a proteinspecifically expressed in brown adipose tissue. Increased metabolicactivity of brown adipose tissue, e.g., in response to cold exposure orto diet, results in increased thermogenesis and heat production. Brownadipocytes, the primary cellular component of brown adipose tissue, arecharacterized by numerous small lipid droplets and much higher numbersof mitochondria relative to white adipocytes. Brown adipose tissue canaffect whole-body metabolism and may alter insulin sensitivity andmodify susceptibility to weight gain. Brown adipose tissue, for example,can have profound effects on body weight, energy balance, plasmatriglyceride levels, and glucose metabolism. Ablation of the growthhormone secretagogue receptor (GHS-R), e.g., by genetic modification,has been associated with enhanced thermogenic capacity and an elevationin brown adipose tissue mitochondria and UCP-1 in older mice and but notin younger mice. This result suggests GHS-R is important in age relateddysfunction of brown adipose tissue. See, e.g., Bartelt et al., Nat Med(2011) Jan. 23, doi:10.1038/nm.2297; Ma et al., PLoS ONE 6(1): e16391.doi:10.1371/journal.pone.0016391. 2011; Richard and Picard, Frontiers inBioscience 16: 1233-1260, 2011; Nedergaard and Cannon Cell Metab 11(4):268-72, 2010, Nedergaard, et al., Am. J. Physiol. Endocrinol. Metab.293: E444s-E452, 2007; Almind, et al., Proc. Natl. Acad. Sci., 104:2366-2371, 2007, each of which is incorporated herein by reference.

The device disclosed herein can include one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectto modulate at least one activity of brown adipose tissue of thevertebrate subject. Modulating the at least one activity of the brownadipose tissue can include, but is not limited to, enhancing metabolicactivity of brown adipose tissue, increasing metabolic activity of brownadipose tissue, or increasing proliferation of brown adipose tissue inthe vertebrate subject. Modulating the at least one activity of thebrown adipose tissue can include, but is not limited to, increasing oneor more of adipogenesis, differentiation, non-shivering thermogenesis,or energy production of the brown adipose tissue in the vertebratesubject. Modulating the at least one activity of the brown adiposetissue can include modulating, e.g., increasing, non-shiveringthermogenesis.

In rodents, brown adipose tissue tends to be localized within theinterscapular, subscapular, renal, and paraspinal regions, whereas inhumans the main depots of brown adipose tissue are supraclavicular,cervical, and paraspinal. Brown adipose tissue functions in cold- anddiet-induced thermogenesis, which significantly contributes to thecontrol of body temperature and energy expenditure (Richards and Picard,ibid). Thermogenesis in brown adipose tissue may represent a defensemechanism against obesity by increasing energy expenditure. Ablation ofbrown adipose tissue in rodents, for example by excision or by using atoxic gene, results in hyperphagia and obesity, supporting a role forbrown adipose tissue in metabolic homeostasis. Likewise, the absence ofbrown adipose tissue activity is more apparent in overweight humans, inparticular those of advancing age, correlating with obesity. Inaddition, a lack of UCP1 activity is sufficient to cause or aggrevateobesity in mice. Considering the advances in studies into human brownadipose tissues, data regarding effects of brown adipose tissue onmetabolism have been extrapolated to human biology, yieldingexplanations for human metabolic phenomena (see e.g. Nedergaard &Cannon, Cell Metab. 11(4): 268-272, 2010, which is incorporated hereinby reference.)

In human neonates, brown adipose tissue is readily detectable, and isknown to provide thermal regulation in the early months following birth.The brown adipose tissue present at birth in humans decreases duringnormal development to adulthood, and, until recently, it was commonlythought that all brown adipose tissue was actually lost within the firstfew years of life. Newer technologies, including positron emissiontomography (PET)-computed tomography (CT) and uptake of radioactivefluorodeoxyglucose (FDG), have now allowed the identification ofmetabolically active brown adipose tissues in human adults. Prospectivestudies using PET-CT with FDG uptake in healthy adult humans indicatehigh prevalence of brown adipose tissue in young adults, with detectionof active brown adipose tissue less apparent in elderly (who tend tohave higher bodyweight) and/or overweight persons. Both the presence andactivity of the brown adipose tissues has been confirmed histologically.See, e.g., Saito, et al., Diabetes 58: 1526-1531, 2009 and Yoneshiro etal., Obesity 19: 13-16, 2011, which are incorporated herein byreference. Conversely, FDG uptake in humans can be inhibited or reversedby exposure to warm conditions. See e.g. Christensen et al., Clin NuclMed. 31(4): 193-6, 2006; and Nedergaard, et al., Am. J. Physiol.Endocrinol. Metab. 293: E444-E452, 2007, each of which is incorporatedherein by reference. Studies indicate a high frequency of presence ofbrown adipose tissue in human adults. In addition, brown adipose tissueis more commonly detected in female, younger, and leaner individuals;fasting glucose levels are lower in individuals with apparent brownadipose tissue; and brown adipose tissue is more detectable inindividuals with lower body weight and fasting glucose levels. Brownadipose tissue in humans and other animals is more active, and moredetectable, at lower temperatures, a reflection of its role incold-induced increases in energy expenditure. Brown adipose tissue islikely present in the majority of adult humans, with variations inactivity and amount arising from factors including environment, age,weight, gender, and glucose levels. See, e.g., Lee, et al., Am J PhysiolEndocrinol Metab 299: E601-E606, 2010; van Marken Lichtenbelt, et al.,N. Engl. Med., 360: 1500-1508, 2009; Cypess, et al., N. Engl. J. Med.,360: 1509-1517, 2009, each of which is incorporated herein by reference.

In mammals, thermogenesis can be induced by thermoregulatory networks inresponse to a cold environment, a fall in core body temperature, and/orthe presence of cytokines in certain tissues, e.g. brown adipose tissue.Temperature information is detected by thermoreceptors located insurface and core body parts and is transmitted to the peri-optic area(POA) of the hypothalamus. Environmental temperatures have direct andmore rapid effects on skin temperature than on the temperatures withinthe body core, so that feed forward thermal afferents from the skinprovide the POA with signals to rapidly initiate cold-defensivethermogenic responses before the body core temperatures are affected.Cutaneous thermoreception and its molecular mechanism in sensationutilize proteins from the transient receptor potential (TRP) family ofcation channels, and different proteins are included in responses todifferent temperature ranges. Thermoreceptive mechanisms also exist inbody core structures, including the brain, spinal cord and abdomen. ThePOA itself contains neurons whose activity is affected by local braintemperature, and temperature changes in the spinal cord can affect theactivity of thermoregulatory neurons in the POA. Splanchnic and vagusnerve afferent fibers distributed in the abdomen and exhibit responsesto temperature changes similar to those of cutaneous thermoreceptors,and visceral thermoreceptors are thought to be important in temperatureregulation. Cold thermal receptors have been identified in differentvagal territories including the gastrointestinal and respiratory tracts,and TRP channels are present in vagal afferent neurons associated withthe gut and in the dorsal horn and dorsal root ganglia. Since responsesin the core are not as rapid as in the skin, these receptors are likelyto be involved in maintaining thermoregulation of basal temperature andin extreme or internal changes. Information from the peripheral and corethermoreceptors, then, travels various pathways to subdivisions of thePOA responsible for thermoregulation, which can include bothnonshivering (brown adipose tissue) and shivering thermogenesis. See,e.g., Morrison and Nakamura, Front. Biosci. 16: 74-104, 2011; Morrison,et al., Exp. Physiol. 93: 773-797, 2008; Zhang et al., Am J PhysiolGastrointest Liver Physiol 286: G983-G991, 2004; Fajardo, et al., TheJournal of Neuroscience, 28(31): 7863-7875, Jul. 30, 2008; Choi & Seol,J. Physiol. Anthropol., 20: 375-377, 2001; each of which is incorporatedherein by reference.

Control of mammalian body temperature in a cold environment can beachieved, in part, through sympathetically regulated, nonshiveringthermogenesis. Exposure to cold temperature signals the sympatheticnervous system, and triggers the release of catecholamineneurotransmitters, e.g., norepinephrine, that stimulates β-adrenergicreceptors, initiating a cascade of intracellular events in the brownadipocytes and resulting in activation of the mitochondrial proteinuncoupling protein 1 (UCP-1). UCP-1 is located in the innermitochondrial membrane and serves to uncouple oxidative phosphorylationby promoting a proton leak across the mitochondrial membrane, therebygenerating heat and lowering ATP synthesis. The major endogenousstimulator of UCP-1 expression and thermogenesis is the β-adrenergicstimulation mediated by catecholamines released from the sympatheticnervous system. β-adrenergic receptors are expressed predominantly inbrown adipose tissue, and stimulation of these receptors increasesoxygen consumption and UCP-1 mRNA expression. See, e.g., Nedergaard &Cannon, Cell Metab. 11(4): 268-272, 2010; Bartness, et al.,International Journal of Obesity 34: S36-S42, 2010; Cannon & Nedergaard,Physiol. Rev. 84: 277-359, 2004; Morrison, et al., Exp. Physiol., 93:773-797, 2008, each of which is incorporated herein by reference.

Increased detection and activity of brown adipose tissue has beenobserved in adult humans under exposure to cold. Thermogenesis in brownadipocytes appears to be a facultative process in that the tissue willbe inactive in warm surroundings but will be acutely activated, withinminutes, when an animal experiences a cold environment. See, e.g.,Nedergaard, et al., Am. J. Physiol. Endocrinol. Metab. 293: E444-E452,2007, and Cannon & Nedergaard, Physiol. Rev. 84: 277-359, 2004, whichare incorporated herein by reference. In human subjects, for example,the metabolic activity of brown adipose tissue as measured by the uptakeof ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and PET imaging is increased insubjects exposed to a cold environment just prior to the imaginganalysis. See, e.g., Lee, et al., Am J Physiol Endocrinol Metab 299:E601-E606, 2010; Saito, et al., Diabetes 58:1526-1531, 2009; Yoneshiroet al., Obesity (2011) 19: 13-16, 2011; van Marken Lichtenbelt, et al.,N. Engl. J. Med., 360: 1500-1508, 2009; and Virtanen, et al., N. Engl.J. Med. 360: 1518-1525, 2009, which are each incorporated herein byreference. The increased activity of brown adipose tissue in response toexposure to cold is facilitated by release of catecholamineneurotransmitters, e.g., norepinephrine, from the sympathetic nervoussystem in response to activation of cold-sensitive thermoreceptors inand on the body. The level of brown adipose tissue sympathetic nerveactivity, and the norepinephrine release and receptor binding determinethe level of thermogenesis by regulating both the activity of lipasesproviding the fuel to the mitochondria and the level of expression ofUCP1 (Cannon & Nedergaard, Physiol. Rev. 84: 277-359, 2004, which isincorporated herein by reference.

Thermogenesis in brown adipose tissue can be regulated by the degree ofactivation and also by the capacity of the brown adipose tissue. Thedegree of activation can be determined by the acute rate of sympatheticstimulation and can be altered within seconds. The capacity of the brownadipose tissue is mainly determined by the chronic level of sympatheticstimulation of the tissue and needs days or weeks to be significantlyaltered. The total amount of brown adipose tissue, and thus the capacityfor non-shivering thermogenesis, is a response to the environmentaltemperature to which the animal is chronically exposed. During long-termexposure, chronic adrenergic stimulation induces progenitor cells in thetissue to proliferate and brown preadipocytes to differentiate (whichcan also be stimulated by PPARg ligands), thereby increasing the totalcapacity of the tissue, a process referred to as recruitment. Thedifferentiation program of brown adipocytes is characterized byinduction of Ucp1 gene expression and mitochondrial biogenesis. Adaptiveincreases in brown adipose tissue amount and activity may be reflectedin seasonal differences of FDG uptake by brown adipose in humans. Inresponse to acute exposure to cold temperatures, activation of brownadipose tissue, e.g., via the β-adrenergic receptors, stimulates thesynthesis of UCP-1 and mitochondrial proteins in the brown adipocytes.Mitochondrial mass can be experimentally increased in brown adipocytesusing a beta adrenergic receptor agonist to activate the β-adrenergicreceptors. See, e.g. Richard & Picard, Front Biosci., 16: 1233-60, 2011;Saito et al., ibid; Au-Yong et al., Diabetes 58: 2583-2587, 2009, eachof which is incorporated by reference.

In general, the accumulation of white adipose tissue, for example due toan imbalance in caloric intake relative to energy expenditure,contributes to increased weight gain and obesity. The pathologicalaccumulation of excess white adipose tissue that characterizes obesityis a major risk factor for the development of other diseases includingType 2 diabetes, cardiovascular disease, hypertension, stroke,arthritis, and various types of cancer. In contrast, brown adiposetissue evolved in mammals to dissipate large amounts of chemical energyas heat. In rodents, the metabolic activity of brown adipose tissueincreases in response to feeding, essentially diet-induced adaptivethermogenesis, and may be a compensatory mechanism to limit excessweight gain and obesity. Rodents lacking the ability to undergo UCP-1dependent thermogenesis are prone to obesity. In humans with limiteddetectable brown adipose tissue, this compensatory mechanism may belacking, and as such, excessive caloric intake may lead to accumulationof fat and weight gain. Activation and/or proliferation of brown adiposetissue and increased thermogenesis may provide a mechanism for limitingand/or reducing weight gain and treating obesity and associatedsecondary diseases. See, e.g., Seale & Lazar, et al., Diabetes, 58:1482-1484, 2009; Cannon & Nedergaard, Proc. Nutr. Soc., 68: 401-407,2009, each of which is incorporated herein by reference.

Metabolically active brown adipocytes can take up glucose from theperipheral circulation. Cold exposure increases glucose utilization inbrown adipose tissue by several fold and is dependent upon intactsympathetic innervations, e.g., localized release of norepinephrine. Inhumans, glucose, in the form of ¹⁸FDG as used for imaging by PET-CT, istaken up into metabolically active brown adipose tissue depots. Suchuptake is increased at lower temperatures. See, e.g., Lee, et al., Am JPhysiol Endocrinol Metab 299: E601-E606, 2010; Saito, et al., Diabetes58: 1526-1531, 2009; Yoneshiro et al., Obesity (2011) 19, 13-16, 2011;van Marken Lichtenbelt, et al., N. Engl. J Med., 360: 1500-1508, 2009;Cypess, et al., N. Engl. Med., 360: 1509-1517; and Virtanen, et al., N.Engl. J Med., 360: 1518-1525, each of which is incorporated herein byreference. Glucose uptake is also reduced by pretreatment withβ-adrenergic blockers. See, e.g., Parysow, et al., Clin Nucl Med., 2007,32(5):351-7 and Söderlund, et al., J. of Nucl. Med. and Mol. Imag 34(7):1018-1022, 2007. Likewise, the level of detectable brown adipose tissueappears to be inversely proportional to blood glucose levels.Individuals with little detectable brown adipose tissue have increasedglucose levels. In patients scanned more than once, lower fastingglucose levels correlated with increased detectable brown adipose tissue(Lee et al., Am J Physiol Endocrinol Metab. 2010 October; 299(4):E601-6). The presence of metabolically active brown adipose tissue canlower the levels of glucose in the blood stream, which may havebeneficial consequences for the treatment of diabetes and othermetabolic disorders including metabolic syndrome. The treatment goal forboth Type 1 and Type 2 diabetes is to maintain the levels of glucose atnear normal levels. As such, controlled modulation of brown adiposetissue activity and thermogenesis can be a mechanism for controlling thelevels of glucose in the blood stream and consequently treatingmetabolic disorders.

With reference to the figures, and with reference now to FIGS. 1 through5, depicted is an aspect of a device, system, or method that can serveas an illustrative environment of and/or for subject mattertechnologies. The specific devices and methods described herein areintended as merely illustrative of their more general counterparts.

Referring to FIG. 1A, depicted is a partial diagrammatic view of anillustrative embodiment of a device 100 including one or more coolingelements 110 applied to one or more tissues of a vertebrate subject tomodulate at least one activity of brown adipose tissue of the vertebratesubject. A programmable controller 180 is operably connected to the oneor more cooling elements 110, wherein the programmable controller 180 isconfigured to provide instructions to the one or more cooling elements110 in response to information regarding one or more physiologicalconditions of the vertebrate subject. The cooling elements 110 includeflexible tubing incorporated into an item of furniture and/or beddingsuch as a pillow 120 on the bed 130 of the subject. The cooling elements110 can contact thermoreceptors associated with the skin, e.g., facialskin, of the subject. The cooling elements 110 are connected through anoutlet 140 and an inlet 150 through the pillow to a refrigeration unit160 to provide a coolant, e.g., refrigerated water, through the flexibletubing of the cooling elements 110. The refrigeration unit 160 isconnected to a power source 170. The power source can be one or more ofa wired power source and/or a wireless power source and a powertransducer. The programmable controller 180 includes an interface 185that is configured to communicate with a hands-free unit 190 such as apiece of jewelry or wrist watch-like accessory on the subject's wrist.The hands-free unit 190 can include or communicate with sensors formonitoring a physiologic condition or indicator thereof such as thelevel of an analyte in blood, e.g., blood glucose, and/or the caloricintake or weight of the subject. The blood glucose levels or caloricintake can be monitored, for example, by transdermal sensing. Thehands-free unit 190 can also or instead include or communicate withsensors configured to analyze content of an outside substance, forexample a food substance about to be ingested, to gather information,for example information on caloric, nutritional, or sugar content. See,e.g., U.S. Patent Application 2010/0125420; 2010/0125419; U.S.2010/0125418; U.S. 2010/0125417; each of which is incorporated herein byreference. The hands-free unit 190 can also use manual input ofinformation, e.g., caloric intake and weight. The hands-free unit 190can also use wired or wireless input, for example from a database, ofinformation, e.g., caloric content of ingested food. Data collected bythe hands-free unit 190 are wirelessly transmitted to the programmablecontroller 180 at the interface 185 at the end of the waking day.

Referring to FIG. 1B, depicted is a partial diagrammatic view of anillustrative embodiment of a device 100 including one or more coolingelements 110 applied to one or more tissues of a vertebrate subject tomodulate at least one activity of brown adipose tissue of the vertebratesubject. A programmable controller 120 is operably connected to the oneor more cooling elements 110, wherein the programmable controller 180 isconfigured to provide instructions to the one or more cooling elements110 in response to information regarding one or more physiologicalconditions of the vertebrate subject. A digital processing unit 195 isoperably connected to the programmable controller 180. The digitalprocessing unit 195 processes data, for example data collected by thehands-free unit 190 from user input or from sensors included in orcommunicating with the hands-free unit. The digital processing unit 195processes data into one or more resulting instructions and provides theone or more instructions to the programmable controller 180. The digitalprocessing unit 195 can be housed in the hands-free unit 190 andcommunicate with the hands-free unit 190 through circuitry and/or cancommunicate with the hands-free unit 190 through wired or wirelessinterface. The digital processing unit 195 can communicate with theprogrammable control 180 through wired or wireless interface. Thecooling elements 110 include flexible tubing incorporated into an itemof furniture and/or bedding such as a pillow 120 on the bed 130 of thesubject. The cooling elements 110 can contact thermoreceptors associatedwith the skin, e.g., facial skin, of the subject. The cooling elements110 are connected through an outlet 140 and an inlet 150 through thepillow to a refrigeration unit 160 to provide a coolant, e.g.,refrigerated water, through the flexible tubing of the cooling elements110. The refrigeration unit 160 is connected to a power source 170. Thepower source can be one or more of a wired power source and/or awireless power source and a power transducer. The programmablecontroller 180 includes an interface 185 that is configured tocommunicate with a hands-free unit 190 such as a piece of jewelry orwrist watch-like accessory on the subject's wrist. The hands-free unit190 can include or communicate with sensors for monitoring a physiologiccondition or indicator thereof such as the level of an analyte in blood,e.g., blood glucose, and/or the caloric intake or weight of the subject.The blood glucose levels or caloric intake can be monitored, forexample, by transdermal sensing. The hands-free unit can also or insteadinclude or communicate with sensors configured to analyze content of anoutside substance, for example, a food substance about to be ingested,to gather information, for example information on caloric or sugarcontent. The hands-free unit 190 can also use manual input ofinformation, e.g., caloric intake and weight, into the device. Thehands-free unit 190 can also use wired or wireless input of information,e.g., caloric content of ingested food. Data collected by the hands-freeunit 190 are wirelessly transmitted to the programmable controller 180via the interface 185, for example at the end of the waking day. Inaddition or instead, data collected by the hands-free unit 190 arecommunicated to the digital processing unit 195, and the digitalprocessing unit 195 processes the data collected by the hands-free unit190 into one or more resulting instruction and provides the one or moreresulting instruction to the programmable controller 180.

Referring to FIG. 1C, depicted is a partial diagrammatic view of anillustrative embodiment of a device 100 including one or more coolingelements 110 applied to one or more tissues of a vertebrate subject tomodulate at least one activity of brown adipose tissue of the vertebratesubject. A programmable controller 120 is operably connected to the oneor more cooling elements 110, wherein the programmable controller 180 isconfigured to provide instructions to the one or more cooling elements110 in response to information regarding one or more physiologicalconditions of the vertebrate subject. A digital processing unit 195 isoperably connected to the programmable controller 180. The device 100 ofFIG. 1C operates in a similar manner to the device 100 of FIG. 1B,except that in the device 100 of FIG. 1C, the digital processing unit195 is physically incorporated into a unit that includes theprogrammable controller 180. The digital processing unit 195 can behoused in or nearby the programmable controller 180, or can beincorporated into the programmable controller 180, and can communicatewith the programmable controller 180 through circuitry and/or throughwired or wireless interface. The digital processing unit 195 housed inor near the programmable control 180 can communicate, e.g. wirelessly,with the hands-free unit 190.

Referring to FIG. 2, depicted is a partial diagrammatic view of anillustrative embodiment of a device 200 including one or more coolingelements 210 applied to an internal tissue 220, for example in theabdomen, of a vertebrate subject to modulate at least one activity ofbrown adipose tissue of the vertebrate subject to treat a disorder,e.g., a metabolic disease such as diabetes, in the vertebrate subject.The device includes a programmable controller 230 operably connected tothe one or more cooling elements 210, wherein the programmablecontroller 230 is configured, e.g., through programming, to control theone or more cooling elements 210 in response to information regardingone or more physiological conditions of the vertebrate subject, e.g.,information regarding blood glucose levels, caloric intake or weight ofthe vertebrate subject. At least a portion of the device is configuredto be implantable 210. The programmable controller 230 can be accessedthrough a user interface 240 to provide programming or to provideinformation regarding the physiological condition, e.g., caloric intakeor weight. The programmable controller 230 can be configured to interactwith a sensor 250, for example an implanted sensor or external sensorfor monitoring blood glucose. The programmable controller 230 can beconfigured or programmed to control the cooling elements 210 in responseto information received from the sensor or from user input. An incision260 in the skin of the subject acts as an entry point through theperitoneum for inlet cooling tubing 270 and outlet cooling tubing 280including cooling fluid, e.g., water. The inlet cooling tubing 270 andoutlet cooling tubing 280 are connected through a port 285 to arefrigeration unit 290 attached to a chair 295.

Referring to FIG. 3, depicted is a partial diagrammatic view of anillustrative embodiment of a device 300 including one or more coolingelements 310, e.g., one or more Peltier devices, configured to beapplied to a nervous tissue, e.g. a hypothalamus 320, in the brain of avertebrate subject to controllably cool the hypothalamus 320 and tomodulate at least one activity of brown adipose tissue of the vertebratesubject to treat a metabolic disease, e.g., diabetes, in the vertebratesubject. The device includes a programmable controller 330 operablyconnected to the one or more cooling elements 310. The programmablecontroller 330 is operably connected to a thermocouple sensor probe 335and is configured, e.g., programmed, to control the one or more coolingelements 310 in response to information regarding one or morephysiological conditions, e.g., a core temperature, of the vertebratesubject. At least a portion of the device is configured to beimplantable into the pre-optic area (POA) of the hypothalamus 320 of thesubject. Direct cooling of the local environment of the POA evokesactivation and thermogenesis in brown adipose tissue. See, e.g.,Morrison & Nakamura, Frontiers in Bioscience 16: 74-104, 2011; Buoyant &Dean, Ann. Rev. Physiol. 48: 639-654, 1986; Passlick-Deetjen &Beddenbender-Stoll, Nephrol. Dial. Transplant., 20: 1784-1789, 2005;each of which is incorporated herein by reference. The implantablecooling element includes a chip-sized Peltier cooling element 310measuring approximately 6 mm by 6 mm can be combined with a finethermocouple probe 335 and a copper heat sink 340. The cooling surface355 of the Peltier device is close to or in contact with a tissuesurface 345 of the subject. This portion of the cooling element can becovered with a fine layer of medical silicone or other biocompatiblemembrane. The copper heat sink 340 is positioned on the heat dissipatingside 350 of the Peltier element and the heat from the copper heat sink340 is transferred to a circulating fluid that is part of a microchannelcooling system 360 flowing between the implanted portion of the coolingelement through a port 365 to a location on the exterior 370 of thesubject onto a neck wrap 375 at the nape of the neck of the subject.Internal heat transferred from the Peltier element 310 into thecirculating fluid 360 is transferred to the external ambient environmentthrough a series of tubes 370 associated with the microchannel coolingsystem. The thermocouple sensor 335 is used to measure the temperatureof the hypothalamus tissue 320 as it is being cooled and can be includedin a closed loop system to modulate the activity of the Peltier element310 to maintain a desired tissue temperature. The thermocouple sensor335 can be connected to a programmable controller 330 of the device. Theprogrammable controller 330 is located on the exterior of the subjectand is incorporated into a dedicated-use handheld device. The handheldprogrammable controller 330 includes a user interface allowing for inputand receipt of information. The handheld programmable controller 330 isoperably connected to the Peltier element 310 and the thermocouplesensor 335 via wireless radio frequency.

Referring to FIG. 4, depicted is a partial diagrammatic view of anillustrative embodiment of a device 400 including one or more coolingelements 410, e.g., endothermal chemical components, configured to beapplied to a lumenal tissue, e.g. a colon 440, of a vertebrate subjectto controllably cool the tissue and to modulate at least one activity ofbrown adipose tissue of the vertebrate subject to treat a disorder, e.g.a metabolic disease such as diabetes, in the vertebrate subject. Thedevice includes a programmable controller 450 operably connected to theone or more cooling elements 410, wherein the programmable controller450 is operably connected to a sensor 470 configured to monitor aphysiological condition or indicator thereof such as the level of ananalyte, e.g. blood glucose, in the subject. The programmable controller450 can control the one or more cooling elements 410 in response toinformation received from the sensors regarding the one or morephysiological conditions of the vertebrate subject. At least a portionof the device 400 is configured to be implantable into the colon 440 ofthe subject. The device includes an implantable portion implanted intothe colon having a cooling element 410 containing an endothermalchemical composition. The implantable portion of the device 400resembles a self-expanding stent including an internal lumen 405 forinsertion into the lower colon. The implantable portion 400 of thedevice includes two sets of micro-reservoirs, 420 and 430, eachcontaining a distinct endothermic chemical, e.g., citric acid and sodiumbicarbonate, which upon mixing in a common chamber 410 draw heat fromthe surrounding environment resulting in cooling. The micro-reservoirs,410, 420, and 430, are incorporated into the wall of the stent-likestructure. Each micro-reservoir, 420, and 430, containing either citricacid or sodium bicarbonate is covered with a gold foil which in thepresence of a triggering event, e.g., a voltage, dissolves and releasesthe contents of the micro-reservoir. The common chamber 410 is in directcontact with the luminal surface of the colon allowing for localizedcooling. The common chamber 410 also includes a semi-permeable diffusionmembrane 460 through which the byproducts of the endothermic reactioncan diffuse out of the chamber 410 and into the lumen of the colon 440.

Referring to FIG. 5, depicted is a partial diagrammatic view of anillustrative embodiment of a device having a programmable controller forcooling an area of the body of a human subject to treat a disorder,e.g., a metabolic disorder such as metabolic syndrome, in the humansubject. Over time the device can further modulate activity of brownadipose tissue by inducing proliferation and differentiation ofadipocytes thus increasing the mass and total activity of the brownadipose tissue. The device can include one or more passive coolingelements 510, including a deep portion 520 and a shallow portion 530,configured to be applied to the pulmonary vein 540 and thermoreceptorstherein, to cool the tissues and to enhance at least one activity ofbrown adipose tissue of the vertebrate subject with minimal energy inputto the device. The device includes a first portion 520 of the one ormore passive cooling elements is configured to be in association withdeep tissue, e.g., pulmonary vein tissue 540, to be cooled, and a secondportion 530 of the one or more passive cooling elements is configured tobe in association with one or more tissues adjacent to an externalepidermal tissue 560 of the vertebrate subject, and wherein at least aportion 520 of the device is configured to be implantable. The passivecooling system includes a series of tubes 550 and a low-energy pump 580that can circulate a fluid, e.g., water in a closed loop through thedeep and shallow portions of the system. The deep portion 520 of thepassive cooling system is implanted in close proximity to or in directcontact with the pulmonary vein 540. The shallow portion 530 of thepassive cooling system is implanted just below the surface of the skin560 where the temperature of the subject is closer to ambienttemperature and heat exchange with the external environment is possible.The shallow portion 530 of the passive cooling system is configured in atentacle-like structure, allowing the fluid to be spread out over alarger surface area 560 to encourage more rapid cooling or equilibriumwith the outside environment. The fluid in the passive cooling system ispumped by a pump 580 from the relatively cooler environment of theshallow portion to the relatively warmer environment of the deep portionof the device. The pump 580 for circulating the fluid through theimplanted passive cooling system can be powered by a body heat energygenerator incorporated into the implanted portion of the device. Thedevice further includes an external programmable controller 590 mountedinto the armrest of the subject's chair or into a watchband. Theprogrammable controller 590 is configured to send wireless instructionsto the implanted passive cooling system 510.

Referring to FIG. 6, depicted is a partial diagrammatic view of anillustrative embodiment of a device 600 including one or more coolingelements 610 configured to be applied to one or more external tissues ofa human subject, for example an external skin surface 625 such as thatlocated in a suprascapular region of a human subject, to modulate atleast one activity of brown adipose tissue of the human subject. Aprogrammable controller 670 is operably connected to the one or morecooling elements 610 and is configured to control the one or morecooling elements 610 in response to information regarding one or morephysiological conditions of the human subject. The cooling elements 610are applied externally to the skin in the suprascapular region of thehuman subject. The cooling elements 610 include flexible tubingincorporated into a flexible padded substrate 620 and are appliedexternally to the skin in the suprascapular region of the human subject.The cooling elements 610 can contact thermoreceptors associated with theskin of the subject. The cooling elements 610 include tubing connectedthrough an outlet 630 and an inlet 640 through the padded substrate 620and through a refrigeration unit 650 that provides cooling to a coolant,e.g., refrigerated water, that flows through the flexible tubing of thecooling elements 610. The refrigeration unit 650 is connected to a powersource 660. The power source 660 can be one or more of a wired powersource and/or a wireless power source and transducer. The programmablecontroller 670 includes a user interface 675 that is configured tocommunicate with a hands-free unit 680 such as a piece of jewelry orwrist watch-like accessory on the subject's wrist. The hands-free unit680 can include or communicate with sensors for monitoring a physiologiccondition or indicator thereof, such as the level of an analyte inblood, e.g., glucose, and/or the caloric intake or weight of thesubject. The blood glucose levels can be monitored, for example, by atransdermal sensor. The hands-free unit 680 can also, or instead,include or communicate with sensors configured to analyze content of anoutside substance, for example a food substance about to be ingested, togather information, e.g., information on caloric or sugar content. See,e.g., U.S. Patent Application 2010/0125420; 2010/0125419; U.S.2010/0125418; U.S. 2010/0125417; each of which is incorporated herein byreference. The hands-free unit 680 can also use manual input ofinformation, e.g., caloric intake and weight, entered into the device.The hands-free unit 680 can also receive wired or wireless input ofinformation, e.g., caloric content of ingested food provided by adatabase in a personal computing device. The hands-free unit 680 canalso utilize manual input of information, e.g. caloric intake andweight, into the device. Information collected by the hands-free device680 is wirelessly transmitted to the programmable controller 670 at theuser interface 675, for example at the end of the waking day or at otherpredetermined times.

Referring to FIG. 7, depicted is a partial diagrammatic view of anillustrative embodiment of a method 701 for modulating an activity ofbrown adipose tissue of a vertebrate subject comprising applying 702cooling to one or more tissues of the vertebrate subject with one ormore cooling elements, wherein the one or more cooling elements areconfigured to lower the temperature of the one or more tissues andthereby modulate at least one activity of the brown adipose tissue ofthe vertebrate subject, and controlling 703 the one or more coolingelements with a programmable controller configured to provideinstructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. The method can further include sensing 704 with oneor more sensors the information regarding the one or more physiologicalconditions and communicating the information from the one or moresensors to the programmable controller. The method can further includesensing 706 with one or more sensors the information regarding the oneor more physiological conditions and communicating the information fromthe one or more sensors to a digital processing unit, processing 707 theinformation with the digital processing unit into at least one resultinginstruction, and providing 708 by the digital processing unit the atleast one resulting instruction to the programmable controller. Themethod can further include providing 705 information from at least oneof a sensor, a timekeeping device, a user interface, and an outsideoperating source to a digital processing unit, processing theinformation with the digital processing unit into at least one resultinginstruction, and providing by the digital processing unit the at leastone resulting instruction to the programmable controller.

Referring to FIG. 8, depicted is a partial diagrammatic view of anillustrative embodiment of a method 801 for modulating an activity ofbrown adipose tissue in a vertebrate subject, where the method includesapplying 802 cooling to one or more tissues of the vertebrate subjectwith one or more cooling elements, wherein the one or more coolingelements 803 are configured to lower the temperature of the one or moretissues and thereby modulate at least one activity of the brown adiposetissue of the vertebrate subject, wherein at least a portion of the oneor more cooling elements is configured to be implantable, andcontrolling 804 the one or more cooling elements with a programmablecontroller configured to provide instructions to the one or more coolingelements in response to information regarding one or more physiologicalconditions of the vertebrate subject. The method further includessensing 805 with one or more sensors the information regarding the oneor more physiological conditions and communicating the information fromthe one or more sensors to the programmable controller. The methodfurther includes sensing 807 with one or more sensors the informationregarding the one or more physiological conditions and communicating theinformation from the one or more sensors to a digital processing unit,processing the information with the digital processing unit into atleast one resulting instruction, and providing by the digital processingunit the at least one resulting instruction to the programmablecontroller. The method further includes receiving 806 the informationregarding the one or more physiological conditions from an outsideoperating source to a receiver including at least one of theprogrammable controller or a digital processing unit.

Referring to FIG. 9, depicted is a partial diagrammatic view of anillustrative embodiment of a method 901 for modulating an activity ofbrown adipose tissue in a vertebrate subject, where the method includesapplying 902 cooling to one or more tissues of the vertebrate subjectwith one or more passive cooling elements, wherein the one or morepassive cooling elements are configured to lower the temperature of theone or more tissues and thereby modulate at least one activity of thebrown adipose tissue of the vertebrate subject, wherein at least aportion of the one or more passive cooling elements 903 is configured tobe implantable, and wherein the one or more passive cooling elementsincludes a first portion configured to be in association with the one ormore tissues to be cooled, and a second portion configured to be placedin association with one or more tissues adjacent to an externalepidermal tissue of the vertebrate subject. The method can furtherinclude controlling 904 the one or more passive cooling elements with atleast one programmable controller operably configured to provideinstructions to the one or more passive cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. The method can further include sensing 905 with oneor more sensors the information regarding the one or more physiologicalconditions and communicating the information from the one or moresensors to at least one programmable controller.

Method for Treating One or More Disorders

The device described herein, including one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectto modulate at least one activity of brown adipose tissue of thevertebrate subject, and a programmable controller configured to provideinstructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject can be used in a method for treating one or moredisorders in the vertebrate subject. The one or more disorders include,but are not limited to, metabolic disorder, overweightedness, obesity,diabetes, dyslipidemia, and metabolic syndrome. Obesity refers to amedical condition in which excess body fat has accumulated to the extentthat it may have an adverse effect on health, leading to reduced lifeexpectancy and/or increased health problems. Obesity is defined as afunction of body weight relative to height (weight in kilograms/heightin meters) as represented by the body mass index (BMI). Individuals witha BMI equal to or exceeding 30 kg/m² are considered obese whereasindividuals with a BMI ranging from 25 kg/m² to 29.9 kg/m² areconsidered overweight. Obesity can be further classified as class I (BMIof 30.0-34.9 kg/m²), class II (BMI of 35.0-39.9 kg/m²), and class III(BMI of equal to or greater than 40 kg/m²). The risk of developing type2 diabetes, hypertension and cardiovascular disease increases withincreasing BMI. See, e.g., Poirier, et al., Circulation, 113: 898-918,2006, which is incorporated herein by reference.

Metabolic disorder generally refers to a broad array of disorderscharacterized by defects that interfere with the body's metabolism, thechemical processes by which a body transforms proteins, carbohydratesand fats into energy. Inherited metabolic disorders are often the resultof inherited genetic defects. Examples of inherited metabolic disordersinclude Tay-Sachs Disease, Leukodystrophies, Lysosomal Disorders, andLipid Storage Disorders, see e.g., information posted on the NationalLibrary of Medicine of the National Institutes of Health Medline Pluswebsite entitled “Metabolic Disorders”(http://www.nlm.nih.gov/medlineplus/metabolicdisorders.html#cat1), whichwas accessed on Feb. 17, 2011. A metabolic disorder can result from adiseased or dysfunctional organ. Diabetes is an example of a metabolicdisorder resulting from a diseased and/or dysfunctional organ, thepancreas. Additional examples of metabolic disorders may include but arenot limited to obesity, metabolic syndrome, impaired glucose tolerance,and dyslipidemias. See, e.g. Golden, et al., J. Clin. Endocrinol. Metab.94: 1853-1878, 2009, which is herein incorporated by reference.

Diabetes, especially diabetes mellitus, refers to a disorder ofcarbohydrate metabolism and is characterized excessive amounts ofglucose in the blood. The two main types of chronic diabetes are Type 1or insulin-dependent diabetes and Type 2 or noninsulin-dependentdiabetes. Type 1 diabetes is characterized by selective destruction ofinsulin-producing β-cells in the pancreas and severe or absolute insulindeficiency. Individuals with Type 1 diabetes are dependent on dailyinsulin administration to keep glucose levels at a near normal level.Type 2 diabetes is characterized by tissue resistance to the action ofinsulin combined with a relative deficiency in insulin secretion. Agiven individual may have more resistance or more β-cell deficiency, andthe abnormality may be mild or severe. Although insulin is produced inthese patients, it is inadequate to overcome the resistance and theblood glucose rises. The impaired insulin action can also affect fatmetabolism resulting in increased free fatty acid flux and triglyceridelevels and reciprocally low levels of high-density lipoprotein (HDL). Amajor risk factor for the development of Type 2 diabetes is beingoverweight or obese. In addition to chronic forms of diabetes, temporaryor early forms of diabetes can occur including prediabetes, whichpresents with blood sugar levels are higher than normal but not highenough to be classified as diabetes, and gestational diabetes, whichoccurs during pregnancy.

Dyslipidemia refers to abnormal concentrations of lipids in the blood.Dyslipidemia can manifest as hyperlipidemia and can include an elevationof plasma cholesterol (hypercholesterolemia), triglycerides(hyperglyceridemia), or both. Dyslipidemia can include elevated orabnormal levels of lipoproteins including low-density lipoprotein (LDL;“bad”) or high-density lipoprotein (HDL; “good”). In Western society,most cases of dyslipidemia are instances of hyperlipidemia.Hyperlipidemia often results from dietary and lifestyle choices, e.g.,eating a high fat diet or smoking. The causes of dyslipidemia can alsobe genetic or secondary. Primary causes of dyslipidemia include singleor multiple gene mutations that lead to the overproduction oftriglycerides and LDL cholesterol or the underproduction or excessiveclearance of HDL cholesterol. Dyslipidemia in adults is commonlyassociated with a sedentary lifestyle coupled with excessive intake ofsaturated fat, cholesterol, and trans-isomer fatty acids. Dyslipidemiacan be secondary to other disorders including diabetes mellitus,metabolic syndrome, hypothyroidism, overuse of alcohol, and chronickidney disease. Dyslipidemias, in particular hypdercholesterolemia, havebeen linked to coronary heart disease and the formation ofatherosclerotic plaques inside blood vessel walls, causing them tothicken and narrow and increasing the risk of heart disease, stroke, andheart attack. Treatment of dyslipidemia focuses primarily on reducinghigh levels of LDL cholesterol and secondarily on treating high levelsof triglycerides, low levels of HDL cholesterol, or causative disorderssuch as diabetes or metabolic syndrome.

Metabolic syndrome refers to a syndrome characterized by the presence ofat least three factors from an established group of traits, and markedby an association between a metabolic disorder and cardiovasculardisease. The factors considered diagnostic criteria for metabolicsyndrome can include abdominal obesity (e.g., excessive adipose tissuein and around the abdomen), elevated serum triglycerides, decreased HDLcholesterol, elevated blood pressure, insulin resistance, and glucoseintolerance. Other factors present can include prothrombotic state(e.g., high fibrinogen or plasminogen activator inhibitor-1 in theblood), and proinflammatory state (e.g., elevated C-reactive protein inthe blood). See, e.g., Alberti, et al., Circulation, 120: 1640-1645,2009, which is incorporated herein by reference.

Device Including One or More Cooling Elements Applied to One or MoreTissues

The device includes one or more cooling elements configured to beapplied to one or more tissues of a vertebrate subject and aprogrammable controller configured to provide instructions to the one ormore cooling elements. The one or more tissues can include, but are notlimited to, a thermoresponsive tissue, e.g. a thermoreceptor-containingtissue. Thermoreceptor-containing tissue refers to tissue having sensoryreceptors responsive to warm or cold stimuli. Nerve endings of sensoryneurons that respond preferentially to cooling are found in the skin butalso occur in the cornea, tongue, bladder, gastric and respiratorytissues. Warm and cold thermoreceptors have also been identified indifferent vagal territories including the gastrointestinal tract and theupper and lower respiratory tract. Thermoreceptive mechanisms also existin body core structures including the brain, spinal cord and abdomen,including in the abdominal viscera, and in or around the great veins inthe upper abdomen and thorax. Thermoreceptors in the abdominal viscerasignal via splanchnic and vagus nerve afferent fibers, and theirresponses to temperature changes are similar to those of cutaneousthermoreceptors. Responses in the core are not as rapid as in the skin,and are likely to be involved in maintaining thermoregulation of basaltemperature and in extreme or internal changes. Responsiveness toexternal cooling of the skin is noted to varying degrees on the face,chest, abdomen, back, upper arm, forearm, back of the hand, palm, thigh,leg, dorsum of the foot, and sole of the foot. The most sensitive areasof skin appear to be on the face and chest while the skin of feetappears to be the least sensitive. See, e.g., Morrison & Nakamura,Frontiers in Bioscience 16: 74-104, 2011; Choi & Seol, J. Physiol.Anthropol., 20: 375-377, 2001, each of which is incorporated herein byreference.

The device including the one or more cooling elements can be applied tothermoresponsive tissue in the central nervous system. Regions of thecentral nervous system that appear to contain thermoresponsive tissueinclude, but are not limited to, portions of the hypothalamus includingthe preoptic area, anterior hypothalamus, and posterior hypothalamus;other portions of the brain including midbrain, medulla, and cortex; andthe spinal cord. See, e.g., Morrison & Nakamura, Frontiers in Bioscience16: 74-104, 2011; Boulant & Dean, Ann. Rev. Physiol. 48: 639-654, 1986,Passlick-Deetjen & Beddenbender-Stoll, Nephrol. Dial. Transplant., 20:1784-1789, 2005, each of which is incorporated herein by reference.Activation of an implantable, closed-loop cooling system with aperistaltic pump and a thermoelectric cooling device has been describedfor cooling specific portions of the central nervous system. See, e.g.,Osorio, et al., Medicon 2007, IFMBE Proceedings, 16: 911-914, 2007 whichis incorporated herein by reference.

Thermoresponsive tissue can refer to tissue in the core of the subject'sbody. Thermoresponsive tissue in the core can include, but is notlimited to, bladder, gastrointestinal tract, abdominal viscera, and deepveins. For example, intralumenal application of cold stimuli to thestomach and small intestines induces abdominal cold sensation and areflex contraction of the stomach. A similar reflex reaction is observedwhen the inner bladder wall is exposed to cold stimuli. See, e.g.,Rawson & Quick, J. Physiol. 222: 665-677, 1972; Villanova, et al., J.Physiol. 502: 215-222, 1997; Jiang, et al., J. Physiol., 543: 211-220,2002, each of which is incorporated herein by reference.

The device including the one or more cooling elements can be applied toone or more tissues that include nervous tissue, cutaneous tissue, coretissue, organ tissue, visceral tissue, respiratory tissue, gastrictissue, adipose tissue, blood vessels, muscle tissue, or combinationsthereof. Tissues may include a thermoresponsive tissue, e.g., athermoreceptor-containing tissue, or may be associated with athermoresponsive tissue. Nervous tissue refers to components of both theperipheral and central nervous systems including, but not limited to,peripheral neurons, spinal cord, and brain. A cutaneous tissue refers toa tissue associated with the skin and can include, but is not limitedto, dermal tissue such as epidermal, dermal, or subdermal tissue. Acutaneous tissue can include a blood vessel, for example a blood vesselthat occurs in vascularized dermal tissue. A cutaneous tissue caninclude a nerve tissue, which can be, for example, a cutaneous nervetissue, a nerve fiber or nerve tissue ending. Cutaneous tissue is awell-known site of thermoreceptor-containing sensory neurons. A coretissue refers to a tissue deep within a body portion and can include,but is not limited to, a visceral tissue; an organ such as a visceralorgan, digestive organ, or cardiopulmonary organ; a musculoskeletaltissue; a central nervous tissue or brain tissue; or one or more lymphvessels or blood vessels, in particular a deep blood vessel. A centralnervous tissue can include, for example, a spinal ganglion, afferent orefferent nerve of the spinal ganglion, or a vagal nerve. Core tissue canbe located in the thorax, abdominal, pelvic, head, and/or limb regions,and can include, but is not limited to, brain, heart, liver, lung,stomach, intestine, urogenital tract, kidney, bladder, secretory organs,skeletal muscle, vasculature, lymph, adipose, and bone. Core tissue canfurther refer to digestive tissue, circulatory tissue, or one or moreblood vessels or lymph vessels. A blood vessel can include one or moregreat blood vessels or large blood vessels, such as a saphenous vein orpulmonary vein. A core tissue or a cutaneous tissue can include athermoresponsive tissue, for example a thermoreceptor-containing tissue.

Brown adipose refers to any of a number of depots of brown adiposetissue, including brown adipocytes and brown adipcocyte precursors, in asubject. The brown adipose tissue may include or be associated with athermoresponsive tissue, e.g., a thermoreceptor-containing tissue. Inrodents, for example, brown adipose tissue is found in two largelobulated masses on the dorsal aspect of the thorax between the scapulaeand to a lesser extent around the aorta and in the hilus of the kidney.Brown adipose tissue is found in human neonates and human adults in anumber of locations including, but not limited to, supraclavicular,paravertebral, mediastinal, para-aortic, and suprarenal areas. See,e.g., Richard and Picard, Frontiers in Bioscience 16: 1233-1260, 2011;Nedergaard, et al., Am. J. Physiol. Endocrinol. Metab. 293: E444-E452,2007; Cypess, et al., N. Eng. J. Med., 360: 1509-1517, 2009; Virtanen,et al., N. Eng. J. Med., 360: 1518-1525, 2009; and van MarkenLichtenbelt, et al., N. Eng. J. Med., 360: 1500-1508, 2009, each ofwhich is incorporated herein by reference.

Device Including One or More Cooling Elements

A device is described herein that includes one or more cooling elementsand a programmable controller configured to provide instructions to theone or more cooling elements in response to information regarding one ormore physiological conditions of the vertebrate subject. The device canbe used for the treatment of a disorder. The device including the one ormore cooling elements can be applied to one or more tissues of thevertebrate subject to modulate at least one activity of brown adiposetissue of the vertebrate subject. The one or more cooling elements caninclude, but are not limited to, one or more electrical coolingelements, one or more Peltier cooling elements, one or more chemicalcooling elements. The one or more cooling elements can further includeone or more heat pumps. The one or more cooling elements can include oneor more nanoparticles, microparticles, paramagnetic particles, magneticparticles, or chemical core particles.

In an aspect, the device including the one or more cooling elements canbe applied directly to the surface of the body, e.g., on the surface ofa cutaneous tissue such as the skin. The one or more cooling elementscan be applied to the skin associated with the face, chest, abdomen,back, upper arm, forearm, back of the hand, palm, thigh, leg, dorsum ofthe foot, sole of the foot, or other body structure. In an aspect, theone or more cooling elements can be inserted into or through a naturalorifice of the subject, e.g. to access a core tissue. Examples of anatural orifice include, but are not limited to, the oral cavity,trachea, esophagus, nose, ear, urethra, anus and vagina. In an aspect,the one or more cooling elements can access a dermal, subcutaneous, orcore tissue through one or more artificial openings. In an aspect, theone or more cooling elements are implantable, e.g. able to be implanteddirectly into or in close proximity to a thermoresponsive tissue orother tissue type. In an aspect, the one or more cooling elements aredirectly inserted into a blood or lymph vessel.

In an aspect, at least a portion of the one or more cooling elements areapplied to a deep portion of the body, while another portion of the oneor more cooling elements is routed to a shallow portion of the body. Thecooling elements can cool the tissue by passive means or by activemeans, or a combination thereof. The cooling elements in the shallowportion of the body can be tentacles near a cutaneous surface, i.e.,implanted just below the skin to enable heat transfer with the externalambient temperature. For example, a first portion of the one or morecooling elements can be implanted into the hypothalamus of the subjectand a second portion of the cooling elements implanted just below theskin at the neckline. The two portions of the one or more coolingelements can form a continuous loop through which a cooling fluid flowsto cool the thermoresponsive tissues, e.g., the tissue in thehypothalamus.

The one or more cooling elements can be configured to attain atemperature from approximately 4° C. to approximately 36° C., atemperature from approximately 12° C. to 20° C., or a temperature fromapproximately 16° C. or lower. In general, the one or more coolingelements applied to one or more tissues can be cooler than the actualtemperature attained by the tissue. For example, the one or more coolingelements can be configured to cool one or more tissues to a temperatureranging from approximately below 37° C. to approximately above 4° C. Theability of a cooling element to cool a tissue to a specific temperatureis dependent upon the specific temperature of the cooling element andthe amount of time the tissue is exposed to the cooling element. Whilecooling specific tissues of the body with the one or more coolingelements, the temperature of the rest of the body is maintained atthermoneutral temperatures, e.g., by using clothing or coverings,including insulated or warmed clothing or coverings.

In an aspect, the one or more cooling elements of the device can includeone or more electrical cooling elements. The one or more electricalcooling elements can include one or more of a thermoelectric module, athermoelectric cooler, a solid-state heat pump, and/or a Peltier coolingelement. In an aspect, the one or more cooling elements of the devicecan include one or more Peltier cooling elements. The Peltier coolingelements can range in size from about 1×2 mm² to about 60×60 mm² (from,e.g., TEC Microsystems GmbH, Berlin, Germany; Eureca Messtechnik GmbH,Koln, Germany). Smaller micro-Peltier coolers with sub-millimeter areashave also been described. See, e.g., Bottner, et al., J.Microelectromechanical Systems, 13: 414-420, 2004, which is incorporatedherein by reference. In an aspect, the cooling element can include anarray of micro Peltier cooling elements. In an aspect, the one or morePeltier cooling elements can be configured for direct contact with theskin of a subject. See, e.g., U.S. Pat. No. 6,023,932, which isincorporated herein by reference. In an aspect, the one or more Peltiercooling elements can be incorporated into a garment or other objectwherein the cold plate of the Peltier is in intimate thermal contactwith the skin of the wearer. See, e.g., U.S. Pat. No. 4,470,263, whichis incorporated herein by reference. The Peltier cooling element canfurther include a thermocouple fixed to the surface of the Peltier tomeasure the actual temperature of the skin or tissue to provide feedbackcontrol of the temperature of the thermode. See, e.g., Craig, et al., J.Neurophysiol., 86: 1459-1480, 2001, which is incorporated herein byreference.

In an aspect, the one or more cooling elements of the device can includeone or more heat pumps. One or more heat pumps can be configured to moveheat from one location, e.g., the target tissue, to another locationusing mechanical work. One common type of heat pump works by exploitingthe physical properties of an evaporating and condensing refrigerant.The refrigerant, in its gaseous state, can be pressurized and circulatedthrough the system by a compressor. On the discharge side of thecompressor, a hot and highly pressurized gas is cooled in a heatexchanger, i.e., a condenser, until it condenses into a high pressure,moderate temperature liquid. The condensed refrigerant then passesthrough a pressure-lowering device like an expansion valve or capillarytube to another heat exchanger where the refrigerant evaporates into agas via heat absorption. The refrigerant then returns to the compressorand the cycle is repeated.

In an aspect, the one or more cooling elements of the device can includeone or more chemical cooling elements. The one or more chemical coolingelements can include one or more chemical refrigerant, e.g., anevaporant. See. e.g., Fajardo et al., J. Neuroscience 28: 7863-7875,2008, which is incorporated herein by reference. Common examples ofchemical refrigerants include, but are not limited to,chlorofluorocarbons (e.g., trichlorofluoromethane,dichlorodifluoromethane, and 1,2-dichlorotetrafluoroethane),hydrochlorofluorocarbons (e.g., chlorodifluoromethane and2,2-dichloro-1,1,1-trifluoroethane), hydrofluorocarbons (e.g.,1,1,1,2-tetrafluoroethane), hydrocarbons (e.g., butane and iso-butane).Other potential chemical refrigerants for use as chemical coolingelements include, but are not limited to, pentane, isopentane, diethylether, methyl formate, hydrogen, helium, ammonia, water, neon, nitrogen,oxygen, argon, carbon dioxide, chloroethylene, chloromethane, sulfurdioxide, ethane, propane, and pentafluoroethane. The one or morechemical cooling elements can include a chemical cooling agent able todirectly cool the tissue, e.g., an agent containing menthol or icillin.The one or more chemical cooling elements can include an endothermalchemical reactant capable of an endothermic reaction, for example,wherein the endothermal chemical reactants are housed in a tubing.

In an aspect, the one or more cooling elements of the device can includeone or more nanoparticles, microparticles, paramagnetic particles,magnetic particles, or chemical core particles. The chemical coreparticles can further include endothermal chemical reactants capable ofan endothermic reaction.

In an endothermic reaction, energy must be absorbed in order for thereaction to proceed. The absorbed energy results in a decrease in thetemperature of the reaction mixture. For example, the combination ofcitric acid solution with sodium bicarbonate results in an endothermicreaction and a decrease in temperature. Other examples include, but arenot limited to, the combination of barium hydroxide octahydrate crystalswith dry ammonium chloride, the combination of ammonium chloride withwater, the combination of thionylchloride with colbalt sulfateheptahydrate, the combination of ammonium nitrate with water, thecombination of potassium chloride with water, and the combination ofethanoic acid with sodium carbonate. The one or more endothermalchemical reactants can be configured for direct contact with the skinand/or core tissue. Alternatively, the one or more endothermal chemicalreactants can be contained in a mixing chamber with at least one surfaceadapted for efficient heat transfer, e.g., a metal plate, the latter ofwhich is in direct contact with the skin and/or core tissue.

In an aspect, the one or more cooling elements include one or moreendothermic biodegradable particles. The one or more endothermicbiodegradable particles can include one or more frozen particlescomposed of water. The frozen particles composed of water can includeany of a number of ice forms including normal hexagonal crystalline ice,ice Ih, and other forms of ice generated at modified temperatures and/orpressures including, but not limited to, ice Ic, ice II, ice III, iceIV, ice V, ice VI, ice VII, ice VIII, ice IX, ice X, ice XI, ice XII,ice XIII, or ice XIV. The one or more endothermic biodegradableparticles can further include one or more frozen particles composed ofhydrogen oxide, helium, neon, krypton, argon, xenon, nitrogen, chlorine,bromine, oxygen, air, carbon dioxide, or a combination thereof. The oneor more frozen particles can include one or more medicament configuredfor delivery to the skin and/or core tissue for treatment of a metabolicdisorder. Methods for preparation and delivery of frozen particles havebeen described in U.S. patent application Ser. Nos. 12/290,664;12/290,671; 12/586,076; 12/384,202; 12/383,264; 12/383,851; and Ser. No.12/590,033, each of which is incorporated herein by reference. The oneor more endothermic biodegradable particles can be configured for director indirect application to the skin and/or to a core tissue and areanticipated to temporarily cool the site while undergoing a phasetransition, e.g., melting, in response to the temperature of the skinand/or core tissue. The one or more endothermic biodegradable particlescan be configured for direct contact with the skin and/or core tissue.Alternatively, the one or more endothermic biodegradable particles canbe contained in a reservoir with at least one surface adapted forefficient heat transfer, e.g., a metal plate, the latter of which is indirect contact with the skin and/or core tissue that includecold-sensitive thermoreceptors.

In an aspect, the one or more cooling elements include a flow system inwhich fluid circulates through a series of tubing or other channels in aclosed cycle. The fluid in the flow system can include a liquid and/or agas. The fluid can be cooled by one or more of an electrical coolingelement, a Peltier cooling element, a heat sink, a chemical coolingelement, a particulate cooling element, or combinations thereof. Atleast a portion of the tubing can be placed in direct contact with theskin or other body parts. For example, insertion of thermodes into thehypothalamus of rhesus monkey can then be connected to a perfusionmanifold and a circulating water bath. See, e.g., Smiles, et al., J.Appl. Physiol., 40: 653-657, 1976, which is incorporated herein byreference. The fluid circulates through the tubing from a coolingelement, e.g., a refrigeration system using a chlorofluorocarbon and/ora Peltier cooling element, to the tissue and back to the coolingelement. The flow system can include a pump configured to pump the fluidthrough the flow system. The one or more cooling elements including aflow system can be incorporated into clothing, e.g., undergarment, vest,jacket, hat, body suit, or wrap, and/or into furniture, e.g., a bedand/or chair. See, e.g., U.S. Patent Applications 2009/0312676;2008/0077211; 2008/0033518; 2009/0308082, each of which is incorporatedherein by reference. In an aspect, the one or more cooling elementsincluding a flow system can be incorporated into bedding including, butnot limited to, pillows, sheets, blankets, or combinations thereof.

In an aspect, the one or more cooling elements can include a system forpassive cooling or active cooling using a heat sink. In general, a heatsink is a term for a component that efficiently transfers heat from oneplace to another, in this case transferring heat associated with a fluidaway from the fluid to facilitate cooling of the fluid. A passive heatsink dissipates heat through natural convection or macroscopic movementof heated molecules from a hot region to a cool region. For example, afluid warmed by interaction with the internal temperature of a subject,e.g., 37° C., will lose heat as it passes from the internal space to anexternal space and is exposed to ambient temperature. For example, afluid warmed by contact with the torso of a subject will lose heat as itpasses from space adjacent to the torso, e.g. under clothing, to anexternal space, e.g. outside of the clothing, and is exposed to ambienttemperature. A heat sink can feature a series of metal tubes in contactwith a metal plate. The tubes are configured to provide maximum surfaceexchange with the cooling metal plate. The heat sink can include ameso-channel design in which fluid flow in a single tube is divided intomultiple smaller tubes and recollects into larger tube at the end of themetal plate system. Jokar, et al., Heat Transfer Engineering, 31: 3-16,2010, which is incorporated herein by reference. The heat sink caninclude microchannel heat exchangers for transferring heat throughmultiple flat fluid-filled tubes containing small channels while airtravels perpendicular to the fluid flow. See, e.g., Lee, et al., HeatMass Transfer, 48: 1688-1704, 2005, which is incorporated herein byreference. The heat sink can include a series of tubes, e.g., metaltubes, in contact with moving air such as a fan configured to move airpast the series of metal tubes.

In an aspect, the one or more cooling elements can include a passive oractive cooling system that includes one or more heat pipes. A heat pipeis a heat transfer system that combines thermal conductivity and phasetransition to efficiently transfer heat between two interfaces. At thehot interface within a heat pipe, a liquid under vacuum in contact witha thermally conductive solid surface turns into a vapor by absorbing thelatent heat of vaporization. The vapor flows through the system becauseof low pressure associated with the system and condenses back into aliquid at the cold interface, releasing the latent heat. For example,the one or more cooling elements can include one or more heat pipeswhich use a fluid that “boils” at body temperature, e.g., 37° C., butre-condenses at ambient temperature, e.g., 20-25° C. The liquid canreturn to the hot interface through either capillary action or gravityaction where it vaporizes once more and repeats the cycle. The internalpressure of the heat pipe can be set or adjusted to facilitate the phasechange. The heat pipe can consist of a sealed pipe or tube with hot andcold ends made of a material with high thermal conductivity such as, forexample, copper, aluminum or titanium. The heat pipe can then be filledwith a coolant or refrigerant under vacuum. Examples of such fluidsinclude, but are not limited to, water, ethanol, acetone, sodium, ormercury.

The one or more heat pipes can further include a structure configured toexert capillary pressure on the liquid phase of the coolant orrefrigerant. The structure can be sintered metal powder or a series ofgrooves, for examples, but in general may be any material capable ofexerting capillary pressure on the condensed liquid to wick it back tothe heated end. Alternatively, gravity or some other source ofacceleration, e.g., provided by pressure and the mechanics of bodymovement, sufficient to overcome surface tension can be used to causethe condensed liquid to flow back to the heated end. In general, heatpipes contain no mechanical moving parts and typically require nomaintenance.

The heat pipes for low temperature applications generally use somecombination of ammonia (at −60° C. to 100° C.), alcohol (methanol at 10°C. to 130° C.; or ethanol at 0° C. to 130° C.), or water (at 30° C. to200° C.) as working fluid. Other fluids or refrigerants can be used.Since the heat pipe contains a vacuum, the coolant can boil and take uplatent heat at well below its boiling point at atmospheric pressure. Forexample, in an evacuated heat pipe, water will boil just slightly aboveits melting point (0° C.). The heat pipe will operate, therefore, whenthe hot end is just slightly warmer than the melting point of theworking fluid. In an evacuated heat pipe, water will boil at just above273° K (0° C.) and so can start to effectively transfer latent heat atthis low temperature. One advantage of heat pipes over many otherheat-dissipation mechanisms is their great efficiency in transferringheat.

The one or more cooling elements can further include one or more ofnanoparticles, microparticles, paramagnetic particles, magneticparticles, chemical core particles, endothermic chemical particles, icebullets, or combinations thereof. Nanoparticles, e.g., copper oxide,copper, and/or aluminum oxide particles (30 nm in diameter) suspended ina refrigerant, e.g., deionized water, ethylene glycol, or oil, to form ananofluid increase cooling efficiency by providing better heat transfer.See, e.g., U.S. Pat. No. 6,221,275; Lee & Choi, “Application of metallicnanoparticle suspensions in advanced cooling systems,” in RecentAdvances in Solids/Structures and Application of Metallic MaterialsInternational Mechanical Engineering Congress and Exposition, Atlanta,Ga., Nov. 17-22, 1996, each of which is incorporated herein byreference.

The one or more cooling elements can include one or more particles thatare paramagnetic or magnetic particles. In general, magnetic cooling ormagnetocaloric effect arises from exposing a magnetic material to achanging magnetic field. In an aspect, the cooling is facilitated byfluid suspensions containing magnetic and/or paramagnetic particles.See, e.g., Oesterreicher & Parker, J. Appl. Phys., 55: 4334-4338, 1984,and Gschneidner & Pecharsky, Int. J. Refrigeration, 31: 945-961, 2008,each of which is incorporated herein by reference.

The one or more nanoparticles, microparticles, paramagnetic particles,magnetic particles, chemical core particles, endothermic chemicalparticles, ice bullets, or combinations thereof can be applied directlyor indirectly to the surface of the skin or to an internal tissue. Oneor more particle types can be directly applied to the surface of theskin or to an internal tissue by release from a reservoir associatedwith the device. In an aspect, the device can be worn by the subject inthe form of an undergarment that is in contact with one or morethermoreceptor-associated areas of the skin. In response to theprogrammable controller, the particles can be released from one or morereservoirs associated with the undergarment and brought into directcontact with the skin. In an aspect, the device can include a catheterfor delivery of one or more particle types to one or more internalthermoreceptor-associated tissues or other internal target tissue. Thecatheter can be placed intravenously for direct access into a bloodvessel; the catheter can be placed subcutaneously into a brown adiposedepot; or the catheter can be placed intraperitoneally to access targettissues in the abdomen. In an aspect, the catheter for delivery of oneor more particle types can be placed into a natural orifice of thesubject, examples of which include, but are not limited to, oral cavity,nasal cavity, ear canal, urethra, vagina, or anus/colon.

In an aspect, the one or more nanoparticles, microparticles,paramagnetic particles, magnetic particles, chemical core particles,endothermic chemical particles, ice bullets, or combinations thereof canbe applied indirectly to the surface of the skin or to an internaltissue. In this instance, the one or more particles types are containedin a compartment of the device wherein the compartment has directcontact with the skin or internal tissue. For example, the one or moreparticle types can be released into a compartment which includes asurface that readily transfers heat, e.g., a conducting metal surface,which is in direct contact with the skin and/or target tissue.

In an aspect, the one or more cooling elements can include one or morefluid-perfused patches. The one or more fluid-perfused patches may beconfigured to be applied to the surface of the skin. The patch size andnumber can vary depending upon the proportion of skin to be cooled. Theone or more fluid-perfused patches can be applied directly to thesurface of the skin, for example using an adhesive material. The one ormore fluid-perfused patches can be associated with a garment worn by thesubject so as to align the patches in contact with the skin and/or anunderlying tissue. The one or more fluid-perfused patches can beassociated with a structure that comes in direct contact with subject,e.g., bedding or a bed, a chair, or other piece of furniture, and alignsthe patches in contact with the target tissue. The fluid-perfusedpatches and/or garment including the fluid-perfused patches can be undercontrol of the programmable controller.

In an aspect, the one or more cooling elements can be part of aclimate-controlled item of clothing, e.g., a fluid-perfusion suit. Thefluid-perfusion suit can include one or more areas of controlledtemperature output. The fluid-perfusion suit can be worn to maintaincore temperature at a set temperature while one or more coolingelements, for example one or more fluid-perfused patches, at one or morelower temperatures can be applied to specific tissue locations to inducenon-shivering thermogenesis in brown adipose tissue. Aclimate-controlled item of clothing, e.g., a fluid-perfusion suit, canbe configured to include an array of tubes incorporated into along-sleeved jacket and/or full-length trousers and/or hood to enabletransport of a cooling fluid to various parts of a body. The array oftubes can be connected to an external device configured to providefluid, e.g., water at one or more temperatures, to the array of tubes,thereby maintaining the temperature in the item of clothing. Theclimate-controlled item of clothing can include a vest with coolinglines connected to an external refrigeration unit (from, e.g., PolarProducts, Inc., Akron, Ohio). Alternatively, the climate-controlled itemof clothing with cooling elements can be self-contained, for exampleutilizing one or more commercially available components such as thoseavailable from Allen Vanguard, Ashburn, Va. In general, the temperatureand flow properties of the fluid within the fluid-perfused patchesand/or climate controlled item of clothing and/or fluid-perfusion suitare under control of the programmable controller.

In an aspect, the one or more cooling elements can be part of a piece offurniture, a furniture covering, and/or a piece of bedding. The one ormore cooling elements can be configured to include an array of tubesconnected to an external device configured to provide fluid, e.g.,water, at one or more temperatures to the tubes, thereby maintainingtemperature to the furniture, furniture covering, or bedding. The one ormore cooling elements can be self-contained.

In an aspect, the one or more cooling elements can include one or morecold packs. The one or more cold packs can be inserted into a piece ofclothing, a piece of furniture, and/or a piece of bedding and beconfigured to apply a cooling temperature to one or more portions of thebody, e.g., a portion of the skin or underlying tissues, to modulateactivity of a brown adipose tissue, for example to induce non-shiveringthermogenesis in brown adipose tissue. The device that includes aprogrammable controller can control flow of a cooling fluid past thecold packs in order to apply a cooling temperature to one or moreportions of the body in response to information regarding one or morephysiological conditions of the vertebrate subject. For example, the oneor more cooling elements can include one or more cold packs insertedinto cooling vests, hats, and/or wraps for neck, wrist, ankle, foot, andtorso (from, e.g., Polar Products, Inc., Akron, Ohio). The one or morecold packs can include cold packs refrozen by placement into arefrigerator or freezer. The one or more cooling elements can includecold packs containing one or more endothermic chemical reactants. See,e.g., U.S. Pat. No. 3,977,202, which is incorporated herein byreference.

Device Including One or More Cooling Elements in Combination with One orMore Neurostimulators Applied to One or More Tissues

The device described herein including one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectand a programmable controller configured to provide instructions to theone or more cooling elements in response to information regarding one ormore physiological conditions of the vertebrate subject can furtherinclude a neurostimulator operating in combination with the one or morecooling elements. The neurostimulator can include but is not limited toan electric neurostimulator, optical neurostimulator, a magneticneurostimulator, an ultrasonic neurostimulator, or a microwaveneurostimulator. In an aspect, the device can include one or moreneurostimulators configured to stimulate nerves involved in inducingthermogenesis in brown adipose tissue. For example, electricalstimulation of the ventromedial hypothalamic nucleus can inducethermogenesis in interscapular brown adipose tissue temperature, asmeasured by a 1 to 2° C. increase. See, e.g., Thornhill & Halvorson, J.Physiol. 426: 317-333, 1990, which is incorporated herein by reference.The one or more neurostimulator can be implanted into or adjacent to thecentral nervous system and be configured to stimulate neurons within athermoregulatory pathway linking the nervous system to the brown adiposetissue. See e.g. Morrison & Nakamura, Front Biosci. 16: 74-104, 2011.Neurostimulation of one or more part of the brain can be used todirectly or indirectly modulate the metabolic activity of brown adiposetissue, e.g. through a sympathetic pathway of the nervous system.Neurostimulation of specific nerves in the brain, e.g., hypothalamicnerves, are linked to localized release of catecholamines, e.g.,norepinephrine, at the site of brown adipose tissue. The one or moreneurostimulator probes can be placed in or near the hypothalamus, aregion of the central nervous system previously shown to be linked toactivation of brown adipose tissue. See, e.g., Morrison, et al., Exp.Physiol., 93: 773-797, 2008, which is incorporated herein by reference.

In an aspect, a method for treating a disorder can include use of thedevice, as described herein, that includes one or more cooling elementsconfigured to be applied to one or more tissues of a vertebrate subjectand a programmable controller configured to provide instructions to theone or more cooling elements in response to information regarding one ormore physiological conditions of the vertebrate, and further includes aneurostimulator for stimulating a nervous tissue. The neurostimulatorused in the treatment method may be included in the device or may be aseparate device. In an aspect, the device can include one or moreneurostimulators configured to stimulate nerves other than thoseassociated with modulating the metabolic activity of brown adiposetissue. For example, neurostimulation of the hypothalamus and/or vagusnerve can be used to curb appetite in subjects. See, e.g., U.S. Pat.Nos. 5,188,104; 5,263,480; 6,129,685, each of which is incorporatedherein by reference. Neurostimulation of the vagus nerve can be combinedwith the one or more cooling elements to provide combined reduction infood intake and increased thermogenesis and heat loss to treat adisorder, e.g., a metabolic disorder such as obesity.

In an aspect, the device can include an electric neurostimulatorcombined with one or more cooling elements. The electric neurostimulatorcan be one or more of a pacemaker-like device which sends electricalimpulses to specific neurons at specific intervals. The electricneurostimulator can be one or more of an implantable microstimulatorsuch as those described in U.S. Patent Applications 2009/0157151 and2009/0149917, each of which is incorporated herein by reference. The oneor more electric neurostimulator can be one or more of an implantableBion® microstimulator, a miniature, self-contained, rechargeableneurostimulator (from Advanced Bionics Corp., CA). The microstimulatorcan include one or more of a rechargeable battery, a radio and antennafor bi-directional telemetry, a programmable microchip, and astimulating electrode. See, e.g., Carbunaru, et al., Proc. 26^(th)Annual International Conf. IEEE EMBS, San Francisco, Calif., USA, Sep.1-5, 2004, pp. 4193-4196, which is incorporated herein by reference. Inan aspect, the neurostimulator can be one or more injectableneurotransponders, wherein each neurotransponder is the size of a grainof salt (about 1 mm in length and 0.25 mm in diameter) and can be linkedtogether to form an array. See, e.g., U.S. Patent Application2009/0198293, which is incorporated herein by reference. In general, theone or more electrical neurostimulators are in wireless communicationwith the device described herein. Examples of other commerciallyavailable neurostimulators include, but are not limited to, Synergy™ andRestore™ (from Medtronic, Minneapolis, Minn.), Eon Mini™ (from St. JudeMedical, Plano, Tex.), and Precision Plus™ (from Boston Scientific,Natick, Mass.).

In an aspect, the device including the one or more neurostimulators foruse in combination with one or more cooling elements can further includeone or more magnetic neurostimulators. For example, the magneticneurostimulator can be in the form of transcranial magnetic stimulationin which a magnetic field is used to generate an electrical current inthe brain. See, e.g., Wassermann, Electroencephalogr. Clin.Neurophysiol., 108: 1-16, 1998, which is incorporated herein byreference.

In an aspect, the device including the one or more neurostimulators foruse in combination with one or more cooling elements can further includeone or more ultrasonic neurostimulators. Ultrasonic neurostimulators areconfigured to deliver focused ultrasound, in pulsed or continuouswaveforms to influence nerve activity through thermal and/or nonthermal(mechanical) mechanisms. The ultrasonic neurostimulator can delivereither low intensity ultrasound from about 30 to 500 mW/cm² and/orhigh-intensity focused ultrasound at power levels up to or exceeding1000 W/cm². See, e.g., Tyler, Neuroscientist, 2010, e-print ahead ofpublication, which is incorporated herein by reference. In an aspect,focused ultrasound can be combined with a magnetic field to induceneurostimulation as described in U.S. Pat. No. 5,476,438, which isincorporated herein by reference.

In an aspect, the device including the one or more neurostimulators foruse in combination with one or more cooling elements can further includeone or more microwave neurostimulators. Focused microwaves at lowerenergies can provide sufficient thermal energy to trigger nervestimulation. For example, microwave amplification through stimulatedemission of radiation (maser) pulses can induce localized human deepbrain stimulation, eliciting an action potential while increasing thebaseline temperature. See, e.g, Pakhomov, et al., Bioelectromagnetics,24: 174-181, 2003; U.S. Pat. No. 7,548,779; Sierra, Current Sci., 98:27-29, 2010, each of which is incorporated herein by reference.

In an aspect, the device including the one or more neurostimulators foruse in combination with one or more cooling elements can further includeone or more optical neurostimulators. The one or more opticalneurostimulators can include a pulsed infrared-laser light that whenapplied to a nerve or nerves elicits an action potential. For example,pulsed, low-energy infrared with wavelengths ranging from 1.80 to 2.1 μmat a stimulation threshold of 0.3-0.4 J/cm² can elicit nerve actionpotentials and at a threshold that is several fold less than thethreshold at which tissue damage occurs. See, e.g., Wells, et al., SPIENewsroom, 10.1117/2.1200605.0233, 2006; Wells, et al., Biophys J, 93:2567-2580, 2007, each of which is incorporated herein by reference.Optical stimulation can also be combined with electrical stimulation toprovide high spatial precision and greater energies without damagingradiant exposure. See, e.g., Duke, et al., J. Biomedical Optics, 14:060501, 2009, which is incorporated herein by reference.

Device Including Programmable Controller in Communication with One orMore Cooling Elements

The device includes one or more cooling elements and a programmablecontroller operably connected to the one or more cooling elements,wherein the programmable controller is configured to provideinstructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. The programmable controller is configured to provideinstructions to the one or more cooling elements in contact with one ormore tissue in response to information regarding one or morephysiological conditions of the vertebrate subject.

The programmable controller can be directed through a number of sourcesincluding, but not limited to pre-programmed information in theprogrammable controller regarding one or more physiological conditionsof the subject, information provided by user input regarding one or moreone or more physiological conditions of the subject, or programmingprovided by a digital processing unit regarding one or morephysiological conditions of the subject.

The device further includes one or more sensors operably connected tothe programmable controller, wherein the programmable controller isconfigured to provide instructions to the one or more cooling elementsin response to information from the one or more sensors regarding one ormore physiological conditions of the vertebrate subject. The one or moresensors can be configured to sense one or more one or more physiologicalconditions, or indicators thereof, of the vertebrate subject. Forexample, the programmable controller can be programmed so that if theskin temperature rises above 32° C., the programmable controllerinstructs the cooling elements to increase cooling but if the skintemperature falls below 24° C., it instructs the cooling elements todecrease cooling. A temperature of 32° C. represents an averagethermoneutral skin temperature while 24° C. represents a skintemperature in the extremities following environmental cold exposure. Ingeneral, the cooling elements can be modulated by the programmablecontroller to keep the skin temperature between approximately 24° C. and32° C. to induce non-shivering thermogenesis in brown adipose tissue ofthe human subject.

The device can further include a digital processing unit able to processinformation regarding the one or more physiological conditions into oneor more resulting instructions and provide the instructions to theprogrammable controller. The digital processing unit can receiveinformation regarding one or more physiological conditions of thesubject from at least one of a sensor, a timekeeping device, a userinterface, and an outside operating source. The digital processing unitcan process that information into at least one resulting instruction,and can provide programming of the resulting information to theprogrammable controller.

The one or more physiological conditions include information regardingone or more analytes in the vertebrate subject including, but notlimited to, a plasma level of one or more metabolic analytes, forexample, blood glucose levels, blood fatty acid levels, blood pressure,heart rate, and cholesterol levels. For example, the device can includea blood glucose sensor operatively linked to the programmablecontroller, optionally through a digital processing unit, to sense thelevels of glucose in the subject. The digital processing unit can alsoreceive data regarding food consumed and can determine an estimate ofcalories ingested at specific times of the day and/or during the courseof the day and provide programming to the programmable controller.Typically, the level of glucose measured in the blood will fluctuatedepending upon when the measurement is taken relative to when the lastmeal was eaten.

The device including the digital processing unit operably connected tothe programmable controller, wherein the digital processing unit can beprogrammable and can include memory such as volatile or non-volatilememory. The at least one digital processing unit can include processorssuch as microprocessors or digital signal processors, and computationalentities such as operating systems, drivers, and applications programs.The at least one digital processing unit can be configured to receiveinformation from at least one of a sensor, a timekeeping device, a userinterface, or an outside operating source. The at least one digitalprocessing unit can be configured to process the information into atleast one resulting instruction and provide the at least one resultinginstruction to the programmable controller. The at least one digitalprocessing unit can be configured to implement logic such as comparison,sorting, reduction, and/or endpoint determination, e.g., relating toinformation regarding one or more physiological conditions of thevertebrate subject. The device can be configured with a digitalprocessing unit configured to collect and analyze multiple data pointsin a relative fashion, including either serially or in parallel, e.g.,relating to information regarding the one or more physiologicalconditions. The system can also include additional sensors, as describedherein, and/or instruments such as a timekeeping device or clock.

In an aspect, the device including the programmable controller canfurther include the combination of the programmable controller and theone or more cooling elements as a single unit. For example, theprogrammable controller can be incorporated into a refrigeration unitthat delivers cooling fluid in one or more tubes of the cooling element,which can be, for example, attached to the skin and/or implanted into aninternal tissue of the subject. In another example, the programmablecontroller can be incorporated into a piece of clothing that alsoincludes the one or more cooling elements.

In an aspect, the device includes a programmable controller whereinaspects of the programmable controller are physically separate from butin communication with the one or more cooling elements. For example, theone or more cooling elements of the device can be implanted into orproximal to an internal tissue of a subject, e.g., the hypothalamus, andreceive instructions regarding control of the one or more coolingelements from an external programmable controller. The externalprogrammable controller can be a computer work station or a handhelddevice that communicates, for example, wirelessly, with the one or morecooling elements implanted in the subject.

In an aspect, the device includes a programmable controller and one ormore cooling elements that are integrated into an implantable singleunit device. The implantable single unit device can functionautonomously without input from an outside source, with the programmablecontroller controlling the function of the cooling elements based oninput from one or more sensors. In this instance, one or more sensorscan also be integrated into the implantable single unit device or can beplaced in one or more locations remote from the implantable device andin wireless communication with the device. One or more digitalprocessing units can also be integrated into the implantable single unitdevice or can be placed in one or more locations remote from theimplantable device and be in wireless communication with the device. Theone or more digital processing units can in communication withadditional aspects of the device including sensors integrated with thedevice. The implantable single unit device, including any integrateddigital processing units, can also be configured to receive informationfrom an external or outside source, for example when changes need to bemade to the device programming. Changes to the device programming can bemade, for example, by the subject, a caregiver, and/or health careprovider. The programmable controller or digital processing unit cancommunicate with other components of the device through a personal areanetwork, for example, using a technology that permits communication overa short range, e.g., 5 to 10 meters using Bluetooth® wirelesscommunication technology.

The one or more sensors configured to sense one or more physiologicalconditions of the vertebrate subject, or indications thereof, can beincorporated into a component of the device that includes one or more ofthe programmable controller, the digital processing unit, and the one ormore cooling elements. For example, one or more sensors configured tomeasure a temperature of a tissue, e.g. a tissue to which one or morecooling elements is applied or a separate tissue, can be associated withthe programmable controller that provide instructions to the one or morecooling elements, for example instructing the cooling elements to coolor not to cool one or more tissues of the subject. As another example,the one or more sensors configured to measure the activity level of asubject can be incorporated into a wrist watch-like accessory that alsoincludes the programmable controller and a digital processing unit. Inan aspect, the one or more sensor can be configured to come into directcontact with the surface of the skin and employ transdermal sensing ofone or more analytes in the subject. For example, sensors included inthe GlucoWatch® (from, Cyngus, Inc. Redwood City, Calif.) are configuredto non-invasively and continuously monitor glucose using transdermalreverse iontophoresis. The digital processing unit receives data fromthe sensor and processes the data into at least one resultinginstruction and provides the at least one resulting instruction to theprogrammable controller, which provides instructions to the one or morecooling elements. Alternatively or in addition, the one or more sensorsproviding information regarding one or more physiological conditions ofthe vertebrate subject, or indicators thereof, can be at one or morelocations remote from the programmable controller and/or the one or morecooling elements. In this instance, data collected by the one or moresensors can be sent via wireless communication to the digital processingunit and/or programmable controller. For example, the one or moresensors can be one or more of an implanted sensing electrode or luminalpressure monitor configured to send data regarding heart rate or bloodpressure to an externally located programmable controller. As anotherexample, the one or more sensors can be one or more of an implantablesensor configured to monitor one or more analytes such as, for example,glucose. See, e.g., U.S. Pat. No. 6,001,067, which is incorporatedherein by reference.

The device including the programmable controller can be configured tocommunicate with an outside operating source. The outside operatingsource can be configured to both transmit and receive data to and fromthe programmable controller or an associated digital processing unit.The outside operating source can be, for example, a computing devicesuch as a personal computing device, smart phone, or personal digitalassistant. The outside operating source can include access to a databasehaving information regarding one or more analyte levels of normalsubjects compared to subjects having a disease or disorder. The outsideoperating source can include database access having informationregarding nonphysiologic information, such as caloric content offoodstuffs. The outside operating source can include a nonphysiologicsensor, for example an electronic food detector that can determine mass,volume, or weight of foodstuff to be eaten by the subject or can measureand quantitate caloric content and nutritional content of foodstuff thatwill be eaten by the subject. Data from the electronic food detector canbe communicated to the digital processing unit or the programmablecontroller. See, e.g., U.S. Patent Application 2010/0125420;2010/0125419; U.S. 2010/0125418; U.S. 2010/0125417; each of which isincorporated herein by reference. The outside operating source caninclude a user input device, a timekeeping device, or a human operator.The outside operating source can be carried by the subject, positionedin a room with the subject, and/or positioned in a location remote fromthe subject. The remote location can be a location outside the immediatelocation of the subject such as, for example, another room, down thehall, down the street, across town, across state, and/or across country.The remote location can include, but is not limited to, a caregiver'sroom, a nurse's station, a health care provider's office or clinic, astudy site, and/or a health department. The outside operating source canfurther include a handheld device carried by another individual, e.g. acaregiver and/or health care provider. The programmable controllerand/or digital processing unit are configured to both transmit andreceive data to and from the outside operating source. The communicationcan be by wireless transmission, phone line, cable line, computernetwork, or other communication transmission line and/or wirelessnetwork. In an aspect, the outside operating source can be a computingdevice.

The device including the programmable controller can include one or moreof a user interface for use by a subject, caregiver, and/or health careprovider to interact with the device. The user interface can include oneor more of a computing device with a display screen, e.g., a monitor orLCD screen, and a keyboard, keypad, or touchpad. The user interface caninclude one or more dedicated handheld device. The user interface can beincorporated into a multipurpose handheld device, e.g., a cell phone, aPDA, a handheld computer, or a wrist watch. The user interface can beused by a subject, a caregiver, a health care provider, or a combinationthereof. The user interface can be used to input information, to receiveinformation, or a combination thereof. Input information can include,for example, current weight, caloric intake, e.g., types of foodconsumed and quantity thereof, desired weight, desired rate of weightloss, for example, 1 to 2 pounds per week. The input information caninclude physiological conditions, or indicators thereof, that aremeasured using clinical assays independent of the device and caninclude, e.g. blood sugar levels, fatty acid levels, cholesterol levels,heart rate, blood pressure, other medical information pertinent to ametabolic disorder. For example, glucose readings from a standardglucose monitor or cholesterol levels measured during a clinical visitcan be entered by the subject, caregiver, and/or health care providerusing the user interface. The user interface can also be used to receiveinformation. Examples of received information can include physiologicalconditions measured or sensed, e.g., metabolic analytes, blood glucoselevels, fatty acid levels; internal temperature of brown adipose tissueassociated with cold-induced thermogenesis; parameters associated withactivity of brown adipose tissue, e.g. glucose accumulation, glyceroland fatty acid release, temperature, norepinephrine; calculated energyexpenditure; calculated caloric intake; or net caloric intake.

The device including the programmable controller, which can include adigital processing unit, can include one or more time-keeping device,for example, a clock. A clock can be configured to provide the time ofday, time of month, and/or time of year in a given global location. Thetime of day is relevant to the metabolic rate of the subject. Forexample, the metabolic rate of nocturnal animals is greater at nightthan during the day, while the metabolic rate of diurnal animals isgreater during the day than at night. For example, day and night rhythmsand the circadian clock have been linked with metabolism and withlipogenic and adipogenic pathways, which has implications for metabolicsyndrome and obesity. See, e.g., O. Froy, Endocrine Reviews 31: 1-24,2009, which is incorporated herein by reference. As such, the functionof the one or more cooling elements can be adjusted to take intoconsideration the anticipated metabolic rate at different times during a24 hour period. The time of month is relevant to the metabolic rate of,for example, female subjects during the menstrual cycle. For example,basal metabolic rate decreases at menstruation and falls to its lowestpoint approximately 1 week before ovulation and subsequently rises untilthe beginning of the next menstrual cycle. See, e.g., Solomon, et al.,Am. J. Clin. Nutr., 36: 611-616, 1982, which is incorporated herein byreference. A clock can be configured to provide elapsed time relative toan event, e.g., food consumption, oscillatory glucose and insulin levelsin the blood, exercise or other activity.

The device including the programmable controller can further includeprogramming, which may be in a digital processing unit, designed tooptimize function of the one or more cooling elements, for example, toinduce weight loss or treat a disorder. The programming includescomputer software or other computing algorithms able to integrateinformation regarding, for example, caloric intake, energy expenditure,and activity of brown adipose tissue to determine the appropriate amountof cooling needed to induce thermogenesis sufficient for weight lossand/or treatment. In general, weight loss is facilitated when the energyexpenditure of the subject exceeds the energy input, e.g., caloricintake, of the subject. Energy expenditure over the course of a 24 hourperiod, for example, includes resting or basal metabolic rate, i.e., theamount of energy required to maintain normal bodily functions at rest;energy expended during activity, e.g., walking or other exercise; andenergy dissipated by thermogenesis in response to controlled cooling oftissue. Programming to induce weight loss takes into consideration thesevarious parameters and compares them with the caloric intake over asimilar period and modulates the cooling elements accordingly toincrease or decrease thermogenesis to modulate the energy expenditureportion of the calculation. The programming also considers the currentweight of the subject, the desired weight of the subject, and thedesired rate of weight loss over a given time.

The device including the programmable controller can further includeprogramming, which may be in digital processing unit, designed to takeinto consideration the basal and resting metabolic rate of the subjectas part of optimizing the function of the one or more cooling elementsto induce weight loss and/or treatment of a disorder. Basal metabolicrate is the minimum number of calories needed to sustain life in afasting, resting individual. Basal metabolic rate can be measuredexperimentally in humans, for example, as the heat output from the bodyper unit time and/or by measuring the rate of oxygen consumption.Measurements are taken 12 to 14 hours after the last meal, completely atrest (but not asleep) and at an environmental temperature of 26-30° C.,to ensure thermal neutrality. Measurement of metabolic rate under lessrigorously controlled conditions can be used to determine the restingmetabolic rate. For individuals with a sedentary lifestyle andrelatively low physical activity, basal metabolic rate accounts forabout 70-80% of total energy expenditure. The parameters of gender,height, weight, age, temperature, muscular activity, ventilationcapacity, caloric intake, drugs, hormones and emotional state for use indetermining basal and/or resting metabolic rate can be entered into theprogrammable controller using the user interface. See, e.g., Lyznicki,et al., Am. Fam. Physician, 63: 2185-2196, 2001, which is incorporatedherein by reference.

The device including the programmable controller can further include adigital processing unit with programming designed to compare theinformation regarding one or more analytes, e.g. metabolic analytes,such as, for example, levels determined by sensors and provided to thedigital processing unit. The digital processing unit with programmingcan be designed to compare the information regarding analyte levels at agiven time with previous measurements or with acceptable norms. When thedigital processing unit determines that the sensed levels of the one ormore analytes are outside the acceptable norms, the digital processingunit provides resulting instructions to the programmable controller thatis configured to take corrective action by providing instruction to thecooling elements to apply cooling to skin or other tissue site, forexample to modulate at least one activity of brown adipose tissue, e.g.inducing non-shivering thermogenesis. For example, normal fasting bloodglucose levels measured 8-12 hours following a meal range from about 70to 100 mg/dL. A normal blood glucose level 2 hours postprandial in anon-diabetic individual is less than 180 mg/dL while the postprandialblood glucose levels in a poorly controlled diabetic will be higher,depending upon how much carbohydrate has been consumed, how much insulinthe subject is producing, and how responsive the subject's insulin is tothe carbohydrate consumed. See, e.g., American Diabetes Association,Diabetes Care, 33: S11-S61, 2010, which is incorporated herein byreference. The digital processing unit can be programmed to process thedata and provide resulting instructions to the programmable controller.The programmable controller then provides instructions to the coolingelements to adjust the cooling, for example to increase cooling toinduce non-shivering thermogenesis and thereby lower glucose levels toapproach a near normal value.

Other analytes and other indicators of physiological conditions in thesubject can be sensed by the sensors and analyzed by the digitalprocessing unit, which processes the information into at least oneresulting instruction and provides the resulting instruction to theprogrammable controller. The programmable control can provideinstructions to the one or more cooling elements in response toinformation regarding one or more physiological conditions of thevertebrate subject. For example, triglycerides can also be analyzed in atissue or fluid of the subject. A level of triglycerides of less than150 mg/dL is considered normal, 150 to 199 mg/dL is borderline high,200-499 mg/dL is high and 500 mg/dL and above is very high. Similarly,high blood pressure is defined as systolic pressure ≧140 mm Hg and/ordiastolic pressure ≧90 mm Hg. In general, the digital processing unit isconfigured to receive data regarding one or more physiologicalcondition, to process the information, for example by comparing the datawith previous data or normal values, into at least one resultinginstruction. The digital processing unit provides the at least oneresulting instruction to the programmable controller to adjust the oneor more cooling elements accordingly in order to modulate at least oneactivity of brown adipose tissue, for example to induce thermogenesis,and treat a disorder.

In an aspect, the programmable controller and/or digital processing unitcan be located external to the body of the subject. The programmablecontroller can be located in the same unit with the one or more coolingelements. For example, the programmable controller and the one or morecooling elements can be incorporated into clothing, e.g., hat, vest,wrap, body suit, pants, shirt; bedding, e.g., pillow, sheet, blanket,mattress pad; furniture, e.g., bed, chair; or other stationary orambulatory object unit. Alternatively, the programmable controller canbe a located in a separate unit relative to one or more external and/orinternal cooling elements. For example, the programmable controller canbe incorporated into a computing device, e.g., a desktop or laptopcomputer; a dedicated handheld device; a multipurpose handheld device,e.g., a cell phone, a PDA, a handheld computer; or other accessory,e.g., a wrist watch-like accessory; in addition to clothing, bedding,furniture, or other object. In an aspect, the external programmablecontroller and the one or more external and/or internal cooling elementscommunicate via a wired connection. In an aspect, the externalprogrammable controller and one or more external and/or internal coolingelements communicate wirelessly, e.g., via Bluetooth® wirelesscommunication, radio frequency, or other wireless communicationmodality.

In an aspect, the programmable controller can be in an internal locationin the body of a subject. The programmable controller can be located inthe same implantable unit with the one or more cooling elements incontact with thermoresponsive tissue. For example, the programmablecontroller and one or more cooling elements can be implanted within orproximal to at least one lumen of a subject, e.g., at least onecirculatory vessel, or the colon or large intestine. Alternatively, theprogrammable controller can be implanted at a location distant from theone or more implanted cooling elements. For example, the programmablecontroller may be implanted near the surface of the skin while the oneor more cooling elements are implanted in or near a deep core tissue.The implanted programmable controller can be in either wired or wirelesscommunication with the implanted one or more cooling elements. In anaspect, the implanted programmable controller can further include one ormore transceiver for sending and receiving data from an external oroutside source.

Device Including One or More Sensors in Communication with ProgrammableController and a Digital Processing Unit

Other components of the device can include at least one digitalprocessing unit operably connected to a programmable controller. Adigital processing unit operably connected to a programmable controllercan be configured to receive at least one signal from one or moresensors, including information regarding one or more physiologicalconditions of a vertebrate subject. The digital processing unit can beprogrammable and can include memory. The at least one digital processingunit can be configured to implement logic such as comparison, sorting,reduction, and/or endpoint determination. The digital processing unitcan be configured to collect and analyze multiple data points in arelative fashion, including either serially or in parallel. The digitalprocessing unit can be operably connected to the programmable controllerand can be configured to receive information from at least one of asensor, a timekeeping device, a user interface, and an outside operatingsource. The digital processing unit can process the information from theone or more sensors into at least one resulting instruction andproviding the at least one resulting instruction to the programmablecontroller.

The programmable controller can be directed through a number of sourcesincluding, but not limited to, pre-programmed information in theprogrammable controller regarding one or more physiological conditionsof the subject; information provided by user input regarding one or moreone or more physiological conditions of the subject; or programmingprovided by the digital processing unit regarding one or morephysiological conditions of the subject.

The programmable controller can be configured to receive at least onesignal from the one or more sensors and to provide instructions in theform of at least one signal to the one or more cooling elements. Thedigital processing units can be configured to receive at least onesignal from the one or more sensors and to process the signal into oneor more resulting instructions and provide the instructions in the formof at least one signal to the programmable controller. The programmablecontroller can be configured to receive at least one signal from the oneor more digital processing units and to provide instructions in the formof at least one signal to the one or more cooling elements. A signal caninclude, for example, an optic signal, a light signal, a chromaticsignal, an acoustic signal, a vibrational signal, an infrared (IR)signal, an electronic signal, a digital signal, a radio signal, awireless signal, or any other detectable signal. A signal from the oneor more sensors, digital processing unit, or programmable controller canbe part of the communication between the one or more sensors, theprogrammable controller, the digital processing unit, and/or the one ormore cooling elements. For example, the programmable controller, thedigital processing unit, or the one or more sensors can be configuredwith one or more transmitter and/or one or more receiver and can utilizefor communication transmissions such as radiowaves. For example, the oneor more sensor may include a means for transmitting radiofrequencysignals and may include, e.g., an analyte sensor-enabled RFID tag (see.,e.g., in Moore, J. Diabetes Sci. Technol. 3: 180-183, 2009, which isincorporated herein by reference). Miniaturized (0.5×0.5×5 mm)Implantable sensors are produced by BIORASIS Inc. including theGLUCOWIZZARD™, an implantable sensor that senses glucose levels andtransmits the information to a proximal communicator. Asyringe-implantable bio-sensor chip can be used that includes a passivetransponder, glucose sensor and integrated circuitry. See, e.g., U.S.Pat. No. 7,125,382 to Zhou entitled “Embedded Bio-sensor System,” whichis incorporated herein by reference. See, e.g., Digital AngelCorporation, St. Paul, Minn. Transmission communications may includefrequency-hopping spread spectrum technology such as Bluetooth® wirelesstechnology. The acoustic transmission communication may includefrequency-hopping spread spectrum technology such as Bluetooth® wirelesstechnology.

The device including one or more signals from the one or more sensorscan be part of the communication between the sensors and the digitalprocessing unit or the programmable controller. A signal from theprogrammable controller can be part of the communication between theprogrammable controller and the one or more cooling elements. Forexample, where the one or more sensors are configured to emit anelectromagnetic signal following detection of a physiological conditionof the subject, the programmable controller can include an EM signaldetection device, such as a detection device configured to detectnon-visible light or light of a specific wavelength. See, for example,U.S. Patent Application No. 2003/0143580 to Straus, titled “Rapid andsensitive detection of molecules,” which is incorporated herein byreference. In embodiments in which the one or more sensors areconfigured to emit optically detectable signals, the one or more sensorscan include, in part or in whole, an optically permeable section (e.g. awindow), and the one or more sensors or the programmable controller caninclude, in part, a spectrophotometer and/or light source configured toelicit signals related to information regarding a physiologicalcondition of the subject. For example, the one or more sensors caninclude at least one of a chromogen, fluorescent agent, luminescentagent, a quantum dot, or a compound configured to exhibit alterableoptical density. A light source associated with the one or more sensorscan include, for example, a light emitting diode or a white lightsource, such as a source configured to provide light in a variableand/or specific wavelength, including infrared (IR) or ultraviolet (UV).See, for example, U.S. Pat. No. 5,183,740 to Ligler et al., titled “Flowimmunosensor method and apparatus,” U.S. Pat. No. 7,459,713 to Coates,titled “Integrated handheld sensing system approach for handheldspectral measurements having a disposable sample handling apparatus,”U.S. Patent Application No. 2008/0265146 to Coates, titled “Integratedsensing module for handheld spectral measurements,” which are hereinincorporated by reference. For example, a sensor pair consisting oflight emitter and light detector can be configured to be a part of theone or more sensors. The digital processing unit sensor can include adigital signal processor and/or software for converting the light signalinto information able to be stored or communicated between the digitalprocessing unit, programmable controller, and sensors. See, for example:U.S. Pat. No. 6,623,698 to Kuo, titled “Saliva-monitoring biosensor headtoothbrush;” U.S. Pat. No. 7,314,453 to Kuo, titled “Handheld diagnosticdevice with renewable biosensor;” U.S. Patent Application No.2003/0023189 to Kuo, titled “Handheld diagnostic device with renewablebiosensor;” and U.S. Patent Application No. 2002/0127143 to Kuo, titled“Saliva-monitoring biosensor electrical toothbrush,” which are hereinincorporated by reference. In some embodiments, the one or more sensorscan use electric pulses to measure the conductivity of one or moretissues of the subject to measure a physiological condition of thesubject, e.g., pH, pCO₂, blood flow, blood pressure, skin temperature,core temperature, tissue temperature, or blood oxygenation. See, forexample, U.S. Pat. Nos. 6,623,698 and 7,314,453 to Kuo.

The device including digital processing unit or programmable controllercan include at least one communication unit including atelecommunication device, a display screen, a speaker, or a printer. Forexample, the programmable controller can be operable connected to atleast one reporting device. The programmable controller, optionally incombination with the digital processing unit, can be operably connectedto at least one reporting device, for example a visual displayconfigured to indicate when a physiological condition in the subject hasbeen detected.

The device including the programmable controller or the digitalprocessing unit can include digital memory. For example, theprogrammable controller or the digital processing unit can includedigital memory, e.g., random access, flash, read only, etc., that isconfigured to record received signals or sent signals, that isinformation regarding one or more physiological conditions of thesubject, e.g., detected substances, time, temperature or pH associatedwith the detection, or other data. For example, the digital processingunit can include digital memory that is configured to include a medicalhistory of the subject. For example, the digital processing unit caninclude digital memory that is configured to include medicalinformation, such as information associating the one or morephysiological conditions detected in the subject with a medical status.

The device including the programmable controller or the digitalprocessing unit can be operably connected to a telecommunication device,which can include an antenna or a cable to transmit and receiveinformation from a network or external computer device, such as ahealthcare system computing device or an individual user's cell phone orpersonal data organizer (PDA). See, for example, U.S. Patent ApplicationNo. 2004/0078219 to Kaylor et al., titled “Healthcare networks withbiosensors;” U.S. Patent Application No. 2004/0100376 to Lye et al.,titled “Healthcare monitoring system;” and Lempert, “Digital housecalls? Check your health at home,” MSNBC Feb. 21, 2006; which areincorporated herein by reference. The programmable controller can alsoinclude additional elements or instrumentation as appropriate to aspecific embodiment.

The device including the digital processing unit or the programmablecontroller can be configured to communicate with at least one network.The network can be a medical network, such as one that includes at leastone medical history, for example a medical history of an individualuser, or of a reference individual or group related to one or morephysiological conditions of the subject. The medical history caninclude, for example, genetic or genomic information, drug use history,allergies, medical diagnoses, or surgical history. A network can be apublic health response network. For example, the digital processing unitincluding the programmable controller can send and receive informationfrom a local health department, such as to report infectious disease orenvironmental conditions that may affect one or more physiologicalconditions in the subject. Information stored on a network or within thedigital processing unit can be accessed at a later time, for example, ifthere is a delayed response by the subject regarding the physiologicalcondition or if there is a later report by another individual.

The device including the digital processing unit or the programmablecontroller can include a telecommunication device, such as atelecommunication device configured to communicate with a network, suchas an area, localized, and/or centralized network. A network can includeone or more database, including, but not limited to, one or more medicalhistory, including for example, genetic or genomic information, drug usehistory, allergies, medical diagnoses, or surgical history. Theprogrammable controller and/or digital processing unit can be configuredas a portion of a network, which might include as a conductive mediumpart or all of the body. See, for example, U.S. Pat. No. 6,754,472 toWilliams et al., titled “Method and apparatus for transmitting power anddata using the human body,” which is incorporated herein by reference.The programmable controller can be configured as a portion of a networkthat is integrated with part or all of a building, such as in a domotic,for instance the MavHome under study at the University of Texas atArlington. The digital processing unit, and the programmable controller,or sensor can form, in part, a personal area network (PAN).

The programmable controller or the digital processing unit can beincorporated into another device, such as an individual user's cellphone, PDA, or laptop. An external device can be configured tocommunicate with the programmable controller or the digital processingunit or one or more sensors that measure the one or more physiologicalconditions of the subject.

The device including the programmable controller or the digitalprocessing unit can include at least one communication device, such as areporting device like a display screen, a speaker, or a printer and canbe configured for interaction with a system user through a userinterface such as a keyboard interface. For example, a communicationdevice can be configured to accept queries or directions from at leastone system user, such as an individual person or a computational,network, or robotic user.

The programmable controller can comprise multiple modules, for instancea handheld module configured to communicate with a separate component.The programmable controller can be configured as a size able to be heldby a human hand, and can be configured to be in communication with theone or more sensors. In some embodiments the programmable controller canbe configured to be wearable by a user, such as on an arm, waist, orback, and can be incorporated into a watch, armband, belt, waistpack,lumbar pack, or backpack. In some embodiments, the programmablecontroller, the digital processing unit and/or the one or more sensorscan be configured to communicate through a wireless connection, such asradio frequency (RF) or other signals.

Device Including One or More Sensors in Communication with ProgrammableController

The device including one or more cooling elements configured to beapplied to one or more tissues of a vertebrate subject to modulate atleast one activity of brown adipose tissue of the vertebrate subject,and a programmable controller configured to provide instructions to theone or more cooling elements in response to information regarding one ormore physiological conditions of the vertebrate subject can furtherinclude one or more sensors operably connected to the programmablecontroller and configured to sense one or more indicator of the one ormore physiological conditions. The one or more sensors can be operablyconnected to the programmable controller through a digital processingunit. The digital processing unit can be operably connected to theprogrammable controller and can be configured to receive informationfrom the sensor, to process the information into at least one resultinginstruction, and to provide the at least one resulting instruction tothe programmable controller. The programmable controller is configuredto provide instructions to the one or more cooling elements in responseto information from the one or more sensors regarding one or morephysiological conditions of the vertebrate subject. The one or moreindicator of the one or more physiological conditions can include aplasma and/or localized tissue level of one or more analytes, e.g. ametabolic analyte, in the subject. In an aspect, the one or moreanalytes can include analytes associated with a disorder. In an aspect,the one or more metabolic analytes can include metabolic analytesassociated with a metabolic disorder. The one or more metabolic analytesindicative of a metabolic disorder include, but are not limited to,glucose, free fatty acids, triglycerides, insulin, glucagon,pro-inflammatory molecules, cholesterol, low density lipoprotein (LDL),and high-density lipoprotein (HDL).

The one or more sensors are configured to provide data to the digitalprocessing unit and/or the programmable controller regarding the plasmaand/or tissue levels of analytes associated with a disorder. Theprogrammable controller is configured to respond to the data receivedfrom the sensors by adjusting the one or more cooling elements toappropriately modulate the activity of brown adipose tissue in order totreat a disorder. Alternatively or in addition, the digital processingunit is configured to process the data from the sensor and provideinstructions and/or programming to the programmable controller to adjustthe one or more cooling elements to appropriately modulate the activityof brown adipose tissue to treat a disorder.

In an aspect, the one or more analytes can include analytes that can beindicative of brown adipose tissue activity. Such analytes include, butare not limited to, utilizable glucose, produced and/or releasedglycerol, free fatty acids, cAMP (indicative of beta-adrenergic receptorstimulation), hexokinase and phosphofructokinase or their enzymaticactivities or products. For example, glucose accumulates in brownadipose tissue activated by exposure to cold. See, e.g., Cypess, et al.,N. Eng. J. Med., 360: 1509-1517, 2009; Virtanen, et al., N. Eng. J.Med., 360: 1518-1525, 2009, each of which is incorporated herein byreference. Similarly, the rate of glycerol and free fatty acid releasefrom brown adipose tissue increases in response to cold acclimation asdoes the enzymatic activity of hexokinase and phosphofructokinase. See,e.g., Rabi, et al., J. Appl. Physiol., 43: 1007-1011, 1977, which isincorporated herein by reference.

In an aspect, the one or more analytes can include a neurotransmitter.The level of norepinephrine increases in brown adipose tissue inresponse to cold exposure. See, e.g., Gabaldon, et al., Am. J. Physiol.Regulatory Integrative Comp. Physiol. 285: 91-98, 2003, which isincorporated herein by reference.

In an aspect, the one or more sensors configured to sense one or morephysiological conditions, or indicators thereof, of the subject. The oneor more physiological conditions can include heat generated bythermogenic activity of the brown adipose tissue. The one or moreanalytes can further include an analyte associated with thermogenicactivity of the brown adipose tissue. To measure one or more analytes orother physiological condition associated with brown adipose tissueactivity, the one or more sensors associated with the device are placedinto or proximal to a depot of brown adipose tissue. The one or moresensors can be configured to provide data to the programmable controlleror digital processing unit regarding analytes associated with theactivity of the brown adipose tissue, for example, measurement of theactivity of uncoupling protein 1 (UCP-1). UCP1, a protein specificallyexpressed in brown adipose tissue, provides an indication of basal andinducible energy expenditure in the form of thermogenesis (i.e., heatproduction) in brown adipose tissue. The digital processing unit can beconfigured to process the information and data received from the sensorsinto at least one resulting instruction and provide the at least oneresulting instruction to the programmable controller. The programmablecontroller can be configured to provide instructions to the one or morecooling elements to alter function appropriately, e.g., by increasing ordecreasing cooling of the tissue, so as to modulate the activity of thebrown adipose tissue.

The device can include one or more sensors configured to sense one ormore other physiological conditions of the subject including, but notlimited to, pH, pCO₂, blood flow, blood pressure, skin temperature, coretemperature, tissue temperature, or blood oxygenation. The one or moresensors can also be configured to sense measures of physical activity ofthe subject as a means for estimating daily energy expenditure. Measuresof physical activity of a subject include, but are not limited to, bodytemperature, heart rate, skin resistance, motion/acceleration, andvelocity.

The one or more sensors operably connected with the programmablecontroller can include, but are not limited to, one or more biosensors,chemical sensors, pressure sensors, temperature sensors, flow sensors,viscosity sensors, shear sensors (e.g., for measuring the effectiveshear modulus of the fluid at a frequency or strain-rate), pH sensors,optical sensors (e.g., charged couple device (CCD) array), opticalwaveguide sensors, acoustic sensors, surface acoustic wave sensors,quartz microbalance sensors, metal oxide sensors, bulk acoustic wavesensors, plate acoustic wave sensors, electrical sensors, magneticsensors, interdigitated microelectrode sensors, electrochemical sensors,electrically conducting sensors, artificial noses, electronic noses,electronic tongues, semiconductive gas sensors, mass spectrometers, nearinfrared and infrared spectrometers, ultraviolet sensors, visiblelight-based sensors, fluorescence spectrophotometers,conductive-polymers, gas-fluorescence spectrophotometers, impedancespectrometers, aptamer-based biosensors, ion mobility spectrometry,photo-ionization detectors, amplifying fluorescent polymer sensors, ionmobility spectrometry, electrical impedance, microgravimetric sensors,cantilever and microcantilever sensors, accelerometers, globalpositioning devices, clocks or time-keeping devices. See, e.g., U.S.Pat. Nos. 5,522,394; 5,873,835; 6,409,674; 6,111,520; 6,278,379;6,475,639; 6,802,811; 6,855,115, 6,517,482; 6,675,030; 6,836,678;6,954,662; 7,184,810; 7,299,080, and U.S. Patent Application2005/0277839, each of which is incorporated herein by reference.

For example, sensors can include a transdermal glucose monitor worn onthe wrist. (GlucoWatch® glucose monitor, Cygnus, Inc. Redwood City,Calif.). The GlucoWatch® glucose monitor is configured to non-invasivelyand continuously monitor glucose using transdermal reverseiontophoresis. After calibration of glucose levels, the glucose monitorbegins monitoring glucose. Batteries produce a small electrical currentthat draws fluid transdermally into the device. Electrode sensorsmeasure the glucose in the fluid. The GlucoWatch® glucose monitorcontains a built-in alarm that can be programmed to alert the user whenresults fall above or below pre-set levels.

The one or more sensors can include a single sensor or an array ofsensors, and is not limited to a particular number or type of sensors.The one or more sensors can be very small, comprising a sensor or arrayof sensors, having, for example, a biosensor, a chemical sensor (SnowScience, 2005, 307: 1942-1945), a gas sensor (Hagleitner et al., Nature,2001 414: 293-296), an electronic nose, a nuclear magnetic resonanceimager (Yusa et al., Nature, 2005, 343: 1001-1005). The foregoingreferences are each incorporated herein by reference. Further examplesof sensors are provided in The Biomedical Engineering Handbook, SecondEdition, Volume I, J. D. Bronzino, Ed., Copyright 2000, CRC Press LLC,pp. V-1-51-9; Morrison et al., “Clinical Applications of Micro- andNanoscale Biosensors” in Biomedical Nanostructures. Edited by K. E.Gonsalves, C. L. Laurencin, C. R. Halberstadt, L. S. Nair. 2008, JohnWiley & Sons, Inc.; and U.S. Pat. No. 6,802,811, each of which isincorporated herein by reference.

The one or more sensors can be configured to detect an analyte thatincludes, but is not limited to, a biological marker, an antibody, anantigen, a peptide, a polypeptide, a neuropeptide, a protein, a complex,an enzyme, a hormone, a neurotransmitter, a nucleic acid, a cell (and,in some cases, a cell of a particular type, e.g. by methods used in flowcytometry), a cell fragment, a cellular component, a platelet, anorganelle, a gamete, a pathogen, a lipid, a lipoprotein, an alcohol, anacid, an ion, an immunomodulator, a sterol, a carbohydrate, asaccharide, a polysaccharide, a glycoprotein, a metal, an electrolyte, ametabolite, an organic compound, an organophosphate, a drug, atherapeutic, a gas, a pollutant, or a tag. The one or more sensors caninclude one or more binding elements configured to interact with ananalyte including, but not limited to, binding molecules, recognitionelements, antibodies or fragments thereof, oligonucleotide or peptidebased aptamers (see, e.g., Mok & Li Sensors 8: 7050-7084, 2008, which isincorporated herein by reference), receptors or ligands, artificialbinding substrates (e.g. those formed by molecular imprinting), or anyother examples of molecules and/or substrates capable of interactingwith an analyte.

In an aspect, the device including the one or more sensors can includeone or more optical sensors. An optical sensor can be configured tomeasure the optical absorption, optical emission, fluorescence, orphosphorescence, luminescence of an analyte or an associated tag orbinding element, or of the brown adipose tissue, other tissues ofinterest, or combinations thereof. Such optical properties can beinherent optical properties of the analyte, e.g. autofluorescence, orcan be optical properties of materials added or introduced into the bodyof the subject that interact with the analyte, the brown adipose tissue,other tissues of interest, or combinations thereof. Optical sensing ofmaterials in blood, for example, is described in Mattley et al., “Bloodcharacterization using UV/VIS spectroscopy” Proc. SPIE Advances inFluorescence Sensing Technology II, Joseph R. Lakowicz; Ed. Vol. 2388,p. 462-470, 1995 and U.S. Pat. Nos. 5,589,932 and 7,027,134, each ofwhich is incorporated herein by reference.

In an aspect, the one or more sensors can be configured to sense theaccumulation of glucose in metabolically active brown adipose tissue. Inthis instance, a fluorescent analogue of glucose can be administeredsystemically, e.g. by the subject or health care provider or by thedevice under the control of the programmable controller, andaccumulation of fluorescence measured in the brown adipose tissuedepots. An example of a fluorescent analogue of glucose is 2-NBDG(2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose) asdescribed in Itoh, et al., J. Cereb. Blood Flow Metab. 24: 993-1003,2004 (commercially available from Molecular Probes, Invitrogen, CarlsbadCalif.). Accumulated fluorescence associated with a fluorescentlylabeled glucose derivative, for example, can be detected in vivo in asubject using an implantable one-chip complementary metal-oxidesemiconductor (CMOS). See, e.g., Tamura, et al., J. Neurosci. Methods,173: 114-120, 2008, which is incorporated herein by reference. Uptake ofglucose in metabolically active brown adipose tissue can also bemeasured using radiolabeled glucose, e.g., fluorodeoxyglucose (¹⁸F-FDG),wherein the sensors are configured to detect the uptake of theradiolabeled glucose. See, e.g., Virtanen, et al., N. Engl. J. Med. 360:1518-1525, 2009, which is incorporated herein by reference.

The device including the one or more sensors can include one or moresensors configured to sense the blood glucose levels in the subject. Theone or more sensors can include a glucose sensor that is either anintegral part of the device, wherein the sensors is operably connectedto the programmable controller as described herein, or is in a separatedevice, for example a glucose sensing device in wireless communicationwith the programmable controller in the device described herein. Anumber of different glucose monitors have been described using, forexample, pin prick, transdermal, or implantable devices. See, e.g., U.S.Pat. Nos. 4,436,094; 4,953,552; 5,497,772; U.S. Patent Applications2010/0049021; 2010/0081910; each of which is incorporated herein byreference. The one or more sensors can include one or moreelectrochemical- or photochemical-based sensors wherein a measurablechemical reaction occurs in response to the presence of one or moreanalyte. For example, many electrochemical sensors use enzymes asspecifiers for the analyte. The enzymes cause a chemical reaction, suchas a reduction reaction, and electrons released by the reaction aretransferred to a mediator molecule, which itself is converted. Themediator then transfers the electrons to an electrode forelectrochemical measurement or transfers the electrons to an indicatormolecule for photochemical responses. Ferrocene derivatives andhexacyanoferrate are examples of one-electron mediators. Quinones are anexample of two-electron mediators. A glucose sensor included in thedevice uses as the specifier an oxidoreductase that oxidizes glucose togluconolactone. Electrons from the glucose are then transferred to theoxidized form of a mediator molecule, which in turn delivers theelectrons to an electrode. The amount of electric current generated isproportional to the amount of glucose in the sample, and electronicswithin the sensor convert the signal, and the signal is communicated tothe programmable controller or the digital processing unit that isoperably connected to the programmable controller. See, e.g., Hones, etal., Diabetes Techn & Therap, 10: Supplement 1 S10-S26, 2008. Examplesof commercially available glucose monitors using such technology inmeasuring blood glucose levels of a subject include, but are not limitedto, OneTouch® blood glucose monitors (LifeScan-Johnson & Johnson,Milpitas, Calif.), Accu-Chek® blood glucose monitors (F. Hoffman-RocheAG, Basel, Switzerland), and Ascencia® blood glucose monitors (BayerHealthCare LLC, Tarrytown, N.Y.). In an aspect, the glucose sensor formeasuring blood glucose levels of a subject can include a continuousmonitoring system, examples of which include, but are not limited toFreestyle Navigator® glucose monitor (Abbot Diabetes Care, Alameda,Calif.), Guardian® Real-Time glucose monitor (Medtronic MiniMed,Northridge, Calif.), and DexCom™ SEVEN® glucose monitor (DexCom, SanDiego, Calif.). See, e.g., Hermanides & DeVries, Diabetologia, 53:593-596, 2010, which is incorporated herein by reference. The FreeStyleNavigator® glucose monitor, for example, is biocompatible chip implantedinto the abdomen or back of the upper arm of a subject and includes anexternal receiver. Similarly, blood glucose sensor-enabled radiofrequency identification (RFID) devices have been described for activemonitoring of glucose. See, e.g., Moore, J. Diabetes Sci. Technol. 3:180-183, 2009, which is incorporated herein by reference. Miniaturized(0.5×0.5×5 mm) implantable glucose sensors can include the GLUCOWIZZARD™implantable glucose sensor that senses glucose levels and transmits theinformation to a proximal communicator. See, e.g., BIORASIS Inc.,Storrs/Mansfield, Conn. A syringe-implantable bio-sensor chip caninclude a passive transponder, glucose sensor, and integrated circuitry.See, e.g., U.S. Pat. No. 7,125,382 to Zhou entitled “Embedded Bio-sensorSystem,” which is incorporated herein by reference. See, e.g., DigitalAngel Corporation, St. Paul, Minn. Other methods for continuousmonitoring of blood glucose levels of a subject include transcutaneousfluorescence lifetime-based microsensors or subcutaneousmicroelectromechanical systems (MEMS)-based sensors. See, e.g., U.S.Pat. No. 6,304,766; Nielsen, et al., J. Diabetes Sci. Technol. 3:98-109; Li, et al., J. Diabetes Sci. Technol. 2: 1066-1074, 2008, eachof which is incorporated herein by reference.

In an aspect, the one or more sensors can use a charged coupled device(CCD) or complementary metal-oxide-semiconductor (CMOS) sensor, forexample, in combination with a binding element that exhibits alteredoptical properties, e.g., fluorescence, in response to binding ananalyte. For example, glycerol and/or free fatty acids can be analyzedusing one or more of the sensors. A sensor for measuring a free fattyacid can include an acyl-CoA-binding protein which exhibits an increasedfluorescence yield in response to binding a fatty acid. See, e.g.,Wadum, et al., Biochem. J., 365: 165-172, 2002, which is incorporatedherein by reference.

In an aspect, the one or more sensor can include a binding element,e.g., an antibody or oligonucleotide aptamer, configured to exhibitFørster or fluorescence resonance energy transfer (FRET) in response tobinding one or more analytes in the subject. FRET is adistance-dependent interaction between the excited states of twofluorophore molecules in which excitation is transferred from a donormolecule to an acceptor molecule without emission of a photon. For usein a sensor, one or more binding molecules, e.g., antibodies oroligonucleotide aptamers, associated with the one or more sensors areconfigured with at least one donor molecule and at least one acceptormolecule. The interaction of an analyte with the binding molecule of thesensor results in a conformation change in the binding molecule, leadingto changes in the distance between the donor and acceptor molecules andchanges in measurable fluorescence.

Donor and acceptor fluorophore pairs can be considered for FRETincluding, but not limited to, fluorescein and tetramethylrhodamine;IAEDANS and fluorescein; fluorescein and fluorescein; and BODIPY FL andBODIPY FL, and various Alexa Fluor pairings as described herein. Thecyanine dyes Cy3, Cy5, Cy5.5 and Cy7, which emit in the red and far redwavelength range (>550 nm) as well as semiconductor quantum dots canalso be used for FRET-based detection systems. Quenching dyes can alsobe used to quench the fluorescence of visible light-excitedfluorophores, examples of which include DABCYL, the non-fluorescingdiarylrhodamine derivative dyes QSY 7, QSY 9 and QSY 21 (MolecularProbes, Carlsbad, Calif., USA), the non-fluorescing Black Hole QuenchersBHQ0, BHQ1, BHQ2, and BHQ3 (Biosearch Technologies, Inc., Novato,Calif., USA) and Eclipse (Applera Corp., Norwalk, Conn., USA). A varietyof donor fluorophore and quencher pairs can be considered for FRETassociated with the binding molecule including, but not limited to,fluorescein with DABCYL; EDANS with DABCYL; or fluorescein with QSY 7and QSY 9. In general, QSY 7 and QSY 9 dyes efficiently quench thefluorescence emission of donor dyes including blue-fluorescentcoumarins, green- or orange-fluorescent dyes, and conjugates of theTexas Red and Alexa Fluor 594 dyes. QSY 21 dye efficiently quenches allred-fluorescent dyes. A number of the Alexa Fluor (AF) fluorophores(Molecular Probes-Invitrogen, Carlsbad, Calif., USA) can be paired withquenching molecules as follows: AF 350 with QSY 35 or DABCYL; AF 488with QSY 35, DABCYL, QSY7 or QSY9; AF 546 with QSY 35, DABCYL, QSY7 orQSY9; AF 555 with QSY7 or QSY9; AF 568 with QSY7, QSY9 or QSY21; AF 594with QSY21; and AF 647 with QSY 21.

The one or more sensors for sensing one or more physiological conditionsof a subject can include surface plasmon resonance (for planar surfaces)or localized surface plasmon resonance (for nanoparticles). Surfaceplasmon resonance involves detecting changes in the refractive index ona sensor surface in response to changes in molecules bound to the sensorsurface. In an aspect, the surface of the sensor is a solid supportcoated with a thin film of metal, e.g., gold. The one or more sensorsinclude a matrix to which is immobilized one or more binding molecules,e.g., antibodies or aptamers, that recognize one or more analytes. Thesensor is illuminated by monochromatic light. Resonance occurs at aspecific angle of incident light. The resonance angle depends on therefractive index in the vicinity of the surface, which is dependent uponthe concentration of analyte bound to the surface. See, e.g., Raghavan &Bjorkman Structure 3: 331-333, 1995, which is incorporated herein byreference.

The one or more sensors for sensing analytes can be one or morelabel-free optical biosensors that incorporate other opticalmethodologies, e.g., interferometers, waveguides, fiber gratings, ringresonators, and photonic crystals. See, e.g., Fan, et al., Anal. Chim.Acta 620: 8-26, 2008, which is incorporated herein by reference. Thelight-based signal or electrical signal to the sensor is converted by atransducer, e.g., within the digital processing unit, into within thedigital processing unit, which then processes the data into informationthat can be stored, analyzed, and communicated, including, for example,at least one resulting instruction. The digital processing unit providesthe at least one resulting instruction to the programmable controller.

The one or more sensors configured to provide information regarding oneor more physiological conditions of the subject can include one or moremicrocantilevers. A microcantilever can act as a biological sensor bydetecting changes in cantilever bending or vibrational frequency inresponse to binding of one or more analytes to the surface of thesensor. See, e.g., Lavrik et al., Rev. Sci. Inst, 75:4: 2229-2253, 2004,which is incorporated herein by reference. In an aspect, the sensor caninclude a microcantilever or a microbead as in an immunoaffinity bindingarray. In another aspect, a biochip can be formed that usesmicrocantilever bi-material, e.g., formed from gold and silicon, assensing elements. See, e.g. Vashist J. Nanotech Online 3: DO:10.2240/azojono0115, 2007, which is incorporated herein by reference.The gold component of the microcantilever can be coated with one or morebinding molecules which upon binding one or more analytes causes themicrocantilever to deflect. Aptamers or antibodies specific for one ormore analytes can be used to coat microcantilevers. See, e.g., U.S. Pat.No. 7,097,662, which is incorporated herein by reference. The one ormore sensors can incorporate one or more methods for microcantileverdeflection detection including, but not limited to, piezoresistivedeflection, optical deflection, capacitive deflection, interferometrydeflection, optical diffraction grating deflection, and charge coupleddevice. The deflection is measured and transmitted as data by atransducer, e.g., within the digital processing unit, which thenprocesses the data into information that can be stored, analyzed, andcommunicated, including, for example, at least one resultinginstruction. The digital processing unit provides the at least oneresulting instruction to the programmable controller. In some aspects,the one or more microcantilevers can be a nanocantilever with nanoscalecomponents. The one or more microcantilevers and/or nanocantilevers canbe arranged into arrays. Both microcantilevers and nanocantilevers canfind utility in microelectomechnical systems (MEMS) and/ornanoelectomechnical systems (NEMS).

The one or more sensors for sensing analytes can include a field effecttransistor (FET) based biosensor. In this aspect, interaction of one ormore analytes with one or more binding elements of the sensor induces anelectrical change that is detected by the transistor. See, e.g., U.S.Pat. No. 7,303,875, which is incorporated herein by reference. Thesignal is processed by the digital processing unit into at least oneresulting instruction. The digital processing unit provides the at leastone resulting instruction to the programmable controller.

The one or more sensors for sensing one or more analytes can incorporateelectrochemical impedance spectroscopy. Electrochemical impedancespectroscopy can be used to measure impedance across a natural and/orartificial lipid bilayer. The sensor can incorporate an artificialbilayer that is tethered to the surface of a solid electrode. One ormore receptor can be embedded into the lipid bilayer. The one or morereceptors can be ion channels that open and close in response to bindingof a specific analyte. The open and closed states can be quantitativelymeasured as changes in impedance across the lipid bilayer. The changesin impedance measured and transmitted as data by a transducer. See,e.g., Yang, et al., IEEE SENSORS 2006, EXCO, Daegu, Korea/Oct. 22-25,2006, which is incorporated herein by reference. The signal is processedby the digital processing unit into at least one resulting instruction.The digital processing unit provides the at least one resultinginstruction to the programmable controller.

The one or more sensors can include cells with binding molecules thatinduce a measurable or detectable change in the cells, e.g., aluminescent signal, when bound to analytes. For example, one can use abioluminescent bioreporter integrated circuit in which binding of ananalyte to an engineered cell induces expression of a reporterpolypeptide linked to a luminescent response. See, e.g., U.S. Pat. No.6,673,596; Durick & Negulescu Biosens. Bioelectron. 16: 587-592, 2001,each of which is incorporated herein by reference. Alternatively, theone or more cell can be engineered to emit an electrical signal inresponse to interacting with one or more analytes. In a further aspect,an implantable biosensor can include genetically modified cells thatrespond to binding analytes by emitting a measurable electrical signalin response to one or more intracellular second messenger molecules thatin turn modulate the activity of one or more ion channels in thegenetically modified cells. The genetically modified cells act as animplantable biosensor that can be coupled via an electrical or opticalinterface to digital processing unit that processes the signal into atleast one resulting instruction and provides the at least one resultinginstruction to a programmable controller. See U.S. Patent Application2006/0234369 A1; which is incorporated herein by reference. In anotheraspect, a biosensor can include a microbial biosensor. For example, amicrobial biosensor and an oxygen electrode can be used to sense freefatty acid. See, e.g., Schmidt, et al., Biosensors Bioelectronics 11:1139-1145, 1996, which is incorporated herein by reference.

The one or more sensors can be configured to include an assembly for invivo microdialysis. In vivo microdialysis allows for continuous samplingfrom the interstitial fluid of a tissue with minimal influence onsurrounding tissues and/or whole body function. A microdialysis probecan be inserted into a tissue of interest, e.g., brown adipose tissue,and perfused at a constant flow rate with a physiological buffer, e.g.,saline. The tip of the probe consists of a semi-permeable membranethrough which compounds in the interstitial fluid of the tissue candiffuse and subsequently be sampled from the outlet tubing of the probe.For example, a linear, implantable microdialysis probe with outlettubing for collection of analytes can be used to measure norepinephrinelevels in brown adipose tissue in response to cold temperature exposure.See, e.g., Gabaldon, et al., Am. J. Physiol. Regulatory IntegrativeComp. Physiol. 285: 91-98, 2003, which is incorporated herein byreference. This technique can also be used to assess lipolytic activityin adipose tissue by measuring glycerol and free fatty acids, theend-products of lypolysis. See, e.g., Flechtner-Mors, et al., J. Pharm.Exp. Ther., 301: 229-233, 2002; Jensen, et al., J. Pharm. Biomed. Anal.,43: 1751-1756, 2007, each of which is incorporated herein by reference.

The one or more sensors can include one or more temperature sensorsconfigured to measure temperature in one or more tissues. For example,temperature sensors can be configured to measure heat generated as aresult of thermogenesis in brown adipose tissue depots. The temperaturesensor can be a thermistor, a thermocouple, or a resistive temperaturedetector. In an aspect, the temperature sensor is a probe thermometerinserted through the skin of the subject and into tissue, e.g., thebrown adipose tissue, with wires extended out into the exterior of thesubject to transmit internal temperature data to the externalprogrammable controller. In an aspect, the temperature sensor is animplantable device that wirelessly transmits internal temperature datato an external programmable controller. An example of an implantabletemperature sensor is described in U.S. Patent Application 2009/0012574,which is incorporated herein by reference. In an aspect, the temperaturesensor is an integral component of a self-contained, fully implantabledevice.

The one or more temperature sensors can further include sensorsconfigured to measure the skin and/or core temperature of the subject.Skin temperature can be measured, for example, using any of a number ofpatch-like temperature sensors (e.g., Level 1™ Skin Temperature Sensor,from Smiths Medical, Dublin, Ohio; VitalSense® Dermal Temperature,Philips—Respironics, Anover, Mass.). Non-invasive surrogate measurementsof core temperature can be taken at a sublingual site, the axilla, andthe tympanic membrane. Invasive measurements of core temperature can betaken using a rectal, esophagus, or gastrointestinal probe. For example,core temperature can be measured using an ingestible telemetrictemperature pill (e.g., CorTemp®, from HQ, Inc., Saratoga, Fla.;VitalSense® Ingestible Capsule, from Philips—Respironics, Anover,Mass.). Temperature sensors can be quite small and integrated into thedevice. For example, the temperature sensors can include one or moresemiconductor thermometers produced in the form of an integratedcircuit, which are available commercially.

The one or more sensors can include one or more sensors that arecalorimeters configured to measure caloric intake and/or energyexpenditure. In an aspect, the one or more calorimeter can include anindirect calorimeter configured to assess the physical activity of thesubject by periodically monitoring heart rate, body temperature, skinresistance, motion/acceleration sensing, velocity and providing anestimate of caloric intake/energy expenditure. The indirect calorimetercan include one or more of a temperature sensor, a heart rate sensor, anaccelerometer, a global positioning system, or a combination thereof.See, e.g., U.S. Patent Application 2009/0240113, which is incorporatedherein by reference. An example of a wireless patch system configuredfor estimating energy expenditure has been described and includessensors, electrodes, and accelerometers. This system measures a varietyof physiological conditions including temperature, heart rate,respiratory rate, and skin conductivity and uses this information in analgorithm to calculate the number of calories consumed, the number ofcalories burned, and the net yield. See, e.g., U.S. Patent Application2010/0049004, which is incorporated herein by reference. Other examplesof calorie counters based on activity measurements have been described.See, e.g., U.S. Pat. Nos. 4,100,401; 4,159,416; 5,815,954; and7,334,472, each of which is incorporated herein by reference. Othermeans for performing calorimetry include, but are not limited to, theHaldane gravimetric method, open-circuit calorimeter with mask,spirographic method, assessment of heat loss and oxygen consumption.

In an aspect, a calorimeter can include a means for manually inputtingdata regarding caloric intake, wherein the food item and quantity eatenby a subject are entered into a software program and the number ofcalories estimated. See, e.g., U.S. Pat. Nos. 5,890,128; and 6,675,041,each of which is incorporated herein by reference. The software programfor entering and estimating the caloric intake can be associated withthe programmable controller of the device or with a digital processingunit of the device operably connected to the programmable controller.Alternatively, the software program can be contained in a separatedevice capable of communication with the programmable controller ordigital processing unit of the device. For example, the software programcan be part of a dedicated handheld device designed for electroniccalorie counting or incorporated into another device such as, forexample, a cell phone, a PDA, a portable laptop, or a wrist watch.

The one or more sensors of the device can be configured to send dataregarding a physiological condition in the vertebrate subject to theprogrammable controller of the device or to a digital processing unitoperably connected to the programmable controller. Conversely, thedigital processing unit can be configured to instruct the one or moresensors to collect and transmit data or other information regarding oneor more physiological conditions or indicators thereof at specifiedregular intervals and/or when triggered by sensed events or byinitiation of particular device activity. The device may further includeinformation storage. For example, measurement of one or morephysiological condition may be collected and stored at specified timeson a daily basis with an associated time stamp. More than onephysiological condition may be measured simultaneously and associatedwith one another during processing. For example, measurement oflocalized brown adipose tissue temperature, or a localized temperatureof an associated nerve tissue or circulatory tissue, can be assessed atthe same time as measurement of blood glucose levels. A temperaturemeasurement can also be triggered by other sensor activity such as whena measured exertion level reaches a specified limit value or immediatelyfollowing caloric intake.

Device Including One or More Cooling Elements in Combination with One orMore Medicaments and Method for Use in Treating a Disorder

The device can be used in a method for treating a disorder in avertebrate subject. The method can include applying cooling to one ormore tissues of the vertebrate subject with one or more coolingelements, wherein the one or more cooling elements are configured tolower the temperature of the one or more tissues and thereby modulate atleast one activity of the brown adipose tissue of the vertebratesubject, and controlling the one or more cooling elements with aprogrammable controller configured to provide instructions to the one ormore cooling elements in response to information regarding one or morephysiological conditions of the vertebrate subject. The method canfurther include providing one or more medicaments in combination withapplying the device configured to cool one or more tissues for thetreatment of a disorder, weight loss, metabolic disorder, diabetes,obesity, metabolic syndrome, or dyslipidemia. The one or moremedicaments can be one or more agents able to modulate (e.g. initiate,induce, enhance, inhibit, or suppress) at least one activity of brownadipose tissue, such as thermogenesis or metabolic activity. The one ormore medicaments can be one or more agents able to modulate at least oneactivity of brown adipose tissue, such as a recruitment, proliferation,differentiation, or adipogenesis. The one or more medicaments can be oneor more agents able to modulate at least one activity of brown adiposetissue can be a neurostimulant. The one or more medicaments can be oneor more agents able to modulate at least one activity of brown adiposetissue and can include, but are not limited to, a β-adrenergic receptoragonist, NPY agonist, leptin, UCP activating agent, thyroxine, serotoninreuptake inhibitor, MCH agonist, GLP-1 agonist, 5-HT2C agonist, 5-HT2Aagonist, galanin antagonist, CRF agonist, urocortin agonist,melanocortin agonist, enterostain agonist, and transcription factor,cAMP analog, bone morphogenetic protein or agonist thereof. Treatment ofa vertebrate subject with medicaments that include natural or syntheticPPARγ ligands can result in recruiting brown adipocytes or inducingproliferation of brown adipocytes in tissues of the vertebrate subject.PRDM16 expression in myoblasts can induce differentiation of myoblastsinto brown adipocytes. PRDM16 stimulates brown adipogenesis by bindingto PPAR and activating PPAR transcriptional function. Treatment of avertebrate subject with medicaments including bone morphogenetic protein7 (BMP7) or analogs thereof has been shown to specifically direct brownadipocyte differentiation in the vertebrate subject. Treatment of avertebrate subject with the device as described herein can include or becombined with one or more medicaments including, but not limited to,cAMP analogs, thyroid hormone, insulin, thiazolidinediones, or retinoicacid, or analogs thereof, that can induce UCP1 expression and inducethermogenesis in brown adipose tissue. See, e.g., Saely, et al., “Brownversus White Adipose Tissue: A Mini-Review,” Gerontology, Karger A G,Basel, Dec. 7, 2010, which is incorporated herein by reference.

The method for treating a disorder in a vertebrate subject can furtherinclude providing the device as described herein in combination with oneor more medicaments configured to treat a metabolic disorder. Themedicaments can include one or more medicaments for the treatment ofweight loss, obesity, diabetes, dyslipidemia, hypercholesterolemiaand/or metabolic syndrome. Examples of medicaments used for weight lossand treatment of obesity include, but are not limited to, lipaseinhibitors (e.g., orlistat), appetite suppressants (e.g., sibutramine,rimonabant, phendimetrazine, diethylpropion, phentermine, bupropio,topiramate, zonisamide), agents that delay gastric emptying (e.g.,hormones and their analogs such as exenatide and pramlintide), andmetformin. Examples of medicaments used for the treatment of diabetesinclude, but are not limited to, insulin, sulfonylurea secretagogues(e.g., tolbutamide, acetohexamide, tolazamide, chlorporpamide,glipizide, glyburide, glimepiride, gliclazide), meglitinidesecretagogues (e.g., repaglinide, nateglinide), biguanide insulinsensitizers (e.g., metformin), thiazolidinediones (e.g., rosiglitazone,pioglitazone), alpha-glucosidase inhibitors (e.g., miglitol, acarbose),glucagon-like peptide analogs and agonists (e.g., exenatide,liraglutide, taspoglutide), dipeptidyl peptidase-4 inhibitors (e.g.,vildagliptin, sitagliptin, saxagliptin), and amylin analogues (e.g.,pramlintide). Examples of medicaments used for the treatment ofdyslipidemia and hypercholesterolemia include, but are not limited to,statins (e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin,pravastatin, rosuvastatin, simvastatin), cholesterol absorptioninhibitors (e.g., ezetimibe), bile acid sequestrants (e.g.,cholestyramine, colestipol), fibrates (e.g., fenofibrate, gemifibrozil),and niacin.

In general, medicaments used to treat obesity, diabetes, dyslipidemia,and hypercholesterolemia as described above are also of use in treatingaspects of metabolic syndrome. Additional aspects of metabolic syndrome,e.g., hypertension, can be treated with anti-hypertensive medicaments.Examples of medicaments for use in treating hypertension include, butare not limited to, diuretics (e.g., chlorthalidone,hydrochlorothiazide, metolazone, spironolactone, bumetanide), betablockers (e.g., acebutanol, metoprolol, propranolol, carteolol,timolol), ACE inhibitors (e.g., benazepril, captopril, enalapril,moexipril), angiotensin II receptor blockers (e.g., candesartan,eprosartan, irbesarten, losartin), calcium channel blockers (e.g.,amlodipine, diltiazem, nifedipine, verapamil), alpha blockers (e.g.,doxazoin, prazosin, terazosin), combined alpha and beta-blockers (e.g.,carvedilol, labetolol), central agonists (e.g., alpha methyldopa,clonidine, guanabenz acetate), peripheral adrenergic inhibitors (e.g.,resiprine, guanadrel), and vasodilators (e.g., hydralazine, minoxidil).

Device Including One or More Cooling Elements in Combination with PowerSource

The device including the one or more cooling elements configured to beapplied to one or more tissues of a vertebrate subject to modulate atleast one activity of brown adipose tissue of the vertebrate subject,and a programmable controller configured to provide instructions to theone or more cooling elements in response to information regarding one ormore physiological conditions of the vertebrate subject, can include atleast one power source configured to power the components of the device.The device can further include one or more sensors and/or one or moreneurostimulators. The power source can be one or more of a wired powersource and/or one or more of a wireless power source. In an aspect, awired power source for powering the device can be derived from astandard electrical outlet. For example, a standard electrical outletcan be used to power an external refrigeration unit that circulatescooling fluid to the skin or internal tissue as well as to power anassociated programmable controller. A wireless power source includesstored power, a battery, or a fuel cell. For an implantable device, thepower source can be external, internal, or a combination thereof. Theimplanted device can be coupled to an external power source through aradio-frequency link. Alternatively, the implanted device can include aself-contained power source made using any means of generation orstorage of energy, e.g., a primary battery, a replenishable orrechargeable battery, a thin film battery, a capacitor, or asupercapacitor. A replenishable or rechargeable self-contained powersource can be replenished or recharged using a radio-frequency link, anoptical link, or other energy-coupling link. See, e.g., U.S. PatentApplication No. 2005/0143787, by B. Boveja, which is incorporated hereinby reference. In an aspect, the power source for an implantable deviceis supplied from an external power source via a transcutaneous inductivecoupling. See, e.g., U.S. Patent Application 2010/0076524, which isincorporated herein by reference.

The power source can include electrical energy generated by mechanicalenergy of a subject's movement. For example, the power source can be alinear motion electric power generator that uses a rare earth magnet anda coil positioned to move linearly back and forth relative to oneanother. The movement of the coil in the field of the magnet generates acurrent in the coil. See, e.g., U.S. Pat. No. 5,347,186, which isincorporated herein by reference. In this instance, power can begenerated as the device moves, e.g., bounces up and down while joggingor while doing other physical activity, as exemplified by the nPower®PEG (Personal Energy Generator, from Tremont Electric, Tremont, Ohio).In an aspect, the power source can be one or more solar panel attachedto one or more component of the device such as, for example, a portablerefrigeration unit in a backpack with affixed solar panels. See, e.g.,U.S. Patent Application 2009/0015022 which is incorporated herein byreference.

In an aspect, the power source can include a rubber film configured toharness energy associated with natural body movements. For example, thepower source can include a material made of a ceramic piezoelectricmaterial, e.g., fabricated lead zirconate titanate that is embedded insilicone rubber sheets. The rubber film can harness natural bodymovements such as walking and breathing as electricity when flexed,converting approximately 80% of mechanical energy into electricalenergy. See, e.g., Qi, et al., Nano Lett., 10: 524-528, 2010, which isincorporated herein by reference.

The power source can include one or more of a battery or microbattery, afuel cell or biofuel cell, or a nuclear battery. One or more powersources of the same or different types can be included in the device,without limitation. Batteries for a small implantable device can includea microbattery, e.g., as available from Quallion LLC, Sylmar, Calif.(http://www.quallion.com), or one designed as a film (U.S. Pat. Nos.5,338,625 and 5,705,293), each of which is incorporated herein byreference. Alternatively, the power source could be one or more fuelcell, for example, a biofuel cell, such as an enzymatic, microbial, orphotosynthetic fuel cell (US2003/0152823A1; WO03/106966A2; or Chen T etal.,” J. Am. Chem. Soc. 2001, 123: 8630-8631, each of which isincorporated herein by reference). The fuel cell can be of any size,including the micro- or nano-scale. In an aspect, the power source caninclude laterally packaged piezoelectric fine wires that convertbiomechanical energy (e.g., stretching muscles, beating heart, walking)into electrical energy using a nanogenerator. See, e.g., Yang et al.,Nature Nanotechnol., 4: 34-39, 2009; Yang et al., Nano Lett., 9:1201-1205, 2009, each of which is incorporated herein by reference. Inanother aspect, the power source can include a pressure-rectifyingmechanism that utilizes pulsatile changes in blood pressure or anacceleration-rectifying mechanism as used in self-winding watches, orother types of flow-rectifying mechanism capable of deriving energy fromother flow parameters. In an embodiment, the power source can be anuclear battery. See, e.g., Wacharasindhut et al., Appl. Phys. Lett.2009, 95: 014103, which is incorporated herein by reference.

In an aspect, the power source can be located remote from the device andcan include an electrical power source connected to the structuralelement by a wire, an optical power source connected to the structuralelement by a fiber-optic line or cable, or a power receiver capable ofreceiving power from an acoustic source or electromagnetic source (e.g.,infrared energy, or inductively coupled, as described in U.S. Pat. Nos.6,170,485, and 7,212,110; U.S. Patent Application No. 2005/0228259; andBudgett et al., J. Appl. Physiol. 2007, 102: 1658-1663, each of which isincorporated herein by reference). The power source can include powergenerated from thermoelectric heating based on the differential betweenbody temperature of a subject and the ambient temperature. See, e.g.,U.S. Pat. No. 6,075,199; U.S. Patent Application 2009/0056328, each ofwhich is incorporated herein by reference. In an aspect, the device caninclude a power transmitter capable of transmitting power (e.g.,acoustic power, electrical power, or optical power) from the device to asecondary location. The secondary location can be, for example, one ormore cooling elements, one or more sensors, another device, orcombinations thereof.

The vertebrate subject can include, but is not limited to, human,equine, bovine, ovine, swine, rodent, canine, feline, avian, amphibian,or reptile.

PROPHETIC EXAMPLES Example 1 Device for Treating Obesity in a HumanSubject Including External Cooling Elements in a Vest

A device is described that includes cooling elements operating under aprogrammable controller for cooling an area of the body of a humansubject to modulate an activity of brown adipose tissue for the purposeof treating obesity in the human subject. The device is incorporatedinto a vest worn by the subject and includes cooling elements in directcontact with thermoreceptors associated with the skin of the subject.The cooling elements have a temperature range from approximately 0° C.to approximately 37° C. to achieve skin temperatures ranging fromapproximately 24° C. to approximately 32° C. to induce non-shiveringthermogenesis in brown adipose tissue of the subject. The deviceincludes a programmable controller operationally linked to multiple skintemperature sensors to control the level of cooling based on sensing theskin temperature of the subject.

The device includes a vest with cooling elements that directly contactthe skin on the chest of the subject. The vest is equipped with an arrayof tubes that circulate a cooling fluid. The cooling fluid, e.g., water,circulates in a closed circuit through the array of tubes and into andout of a refrigeration unit. The refrigeration unit is positioned on theback of the vest. The refrigeration unit includes an array of Peltierelements that cool the circulating water and a small fan that dissipatesthe heat generated by the Peltier elements. A method for circulatingcooling water with an array of Peltier elements is described in U.S.Pat. No. 4,829,771, which is incorporated herein by reference. The wateris pumped from the refrigeration unit through an input tube and thenspreads out into an array of smaller diameter tubes incorporated intothe front surface of the vest. The circulating water is re-collectedinto an output tube and re-circulated back into the refrigeration unitfor re-cooling. The Peltier element for cooling the water and the pumpfor circulating the water are powered using a rechargeable battery pack.

In another vest configuration, water cooling is facilitated bylong-lasting freezer inserts in the refrigeration unit placed into theback of the vest. The back of the vest is well insulated in order toprevent the freezer inserts from uncontrollably cooling the skin of thesubject's back and to prolong the cooling capacity of the freezerinserts. The water in the closed loop is controllably pumped past thefreezer inserts and circulated to the front of the vest to cool the skinon the subject's chest.

The temperature and flow rate of the water through the array of tubes inthe vest is controlled by a programmable controller in a wiredconnection to sensors and to control cooling elements of the vest. Theprogrammable controller includes a user interface for inputting andreceiving data, and a keypad and display screen. The programmablecontroller can control the output from the refrigeration unit based oninput from temperature sensors in contact with the surface of the skinon the chest of the subject. The temperature sensors can sense the skintemperature and transmit this information to the programmablecontroller. The skin temperature sensors are integrated into the vestand in a wired connection to the programmable controller. The skintemperature sensors are oriented in the vest so that the sensors contactthe subject's skin at sites distinct from the sites of active cooling.The skin temperature sensors are adapted from skin temperature sensorsused for monitoring neonatal temperatures (e.g., Neo-Therm® SkinTemperature Sensor, from Smiths Medical, Dublin, Ohio). The programmablecontroller has been programmed so that if the skin temperature risesabove 32° C., it instructs the cooling elements to increase cooling butif the skin temperature falls below 24° C., it instructs the coolingelements to decrease cooling. A temperature of 32° C. represents anaverage thermoneutral skin temperature while 24° C. represents a skintemperature in the extremities following environmental cold exposure. Ingeneral, the cooling elements are modulated by the programmablecontroller to keep the skin temperature between approximately 24° C. and32° C. to induce non-shivering thermogenesis in brown adipose tissue ofthe human subject. The programmable controller, cooling system and skintemperature sensors of the device are wired together in the vest and arepowered by a rechargeable battery pack.

Example 2 Device for Treating Obesity in a Human Subject IncludingExternal Cooling Peltier Elements in a Vest

A device is described that includes cooling elements operating under aprogrammable controller for cooling an area of the body of a humansubject to modulate an activity of brown adipose tissue for the purposeof treating obesity in the human subject. The device is incorporatedinto a vest worn by the subject and includes a number of small Peltierelements incorporated directly into the vest and positioned such thatthe cold surface of the Peltier elements are in contact with the skin ofthe subject, and the hot surface of the Peltier elements dissipates heatto the ambient environment on the outside surface of the vest. ThePeltier elements have a temperature range from approximately 0° C. toapproximately 37° C. to achieve skin temperatures ranging fromapproximately 24° C. to approximately 32° C. and thereby inducenon-shivering thermogenesis in brown adipose tissue of the subject. Thedevice includes a programmable controller operationally linked tomultiple skin temperature sensors to control the level of cooling basedon sensing the skin temperature of the subject.

The Peltier elements are controlled by a programmable controllerincorporated into the vest. The programmable controller includes anattached user interface for inputting and receiving data and a keypadand a display screen. The programmable controller can control thecooling output from Peltier elements based on input from temperaturesensors placed on the surface of the skin on the chest of the subject.The temperature sensors are dermal temperature patches attached to theface of the vest adjacent to the skin at one or more locations on thesubject's skin and in wireless communication with the programmablecontroller associated with the cooling vest (e.g., Dermal TemperaturePatch, from Philips-Respironics, Andover, Mass.). The programmablecontroller has been programmed so that if the skin temperature risesabove 32° C., it instructs the cooling elements to increase cooling butif the skin temperature falls below 24° C., it instructs the coolingelements to decrease cooling. A temperature of 32° C. represents anaverage thermoneutral skin temperature while 24° C. represents a skintemperature in the extremities following environmental cold exposure. Ingeneral, the Peltier elements are modulated by the programmablecontroller to keep the skin temperature between approximately 24° C. and32° C. to induce non-shivering thermogenesis in brown adipose tissue ofthe human subject. The cooling system and the programmable controllerare powered by mechanical energy generated by the movements of thesubject using an nPower® Personal Energy Generator (from TremontElectric, Tremont, Ohio) incorporated into the back of the vest.

Example 3 Device for Facilitating Weigh Loss in a Human SubjectIncluding External Cooling Elements Contacting Facial Skin

A device is described that includes cooling elements operating under aprogrammable controller for cooling an area of the body of a humansubject to modulate an activity of brown adipose tissue brown adiposetissue to facilitate weight loss in the human subject. The device isincorporated into a sleeping surface, e.g., a pillow, and includescooling elements in direct contact with facial skin of the subject andin contact with the thermoreceptors associated the facial skin. Thecooling elements have a temperature range from approximately 0° C. toapproximately 37° C. to achieve a range of tissue temperatures rangingfrom approximately 24° C. to approximately 32° C. to inducenon-shivering thermogenesis in brown adipose tissue of the subject. Thedevice includes a programmable controller and a digital processing unitoperably connected to the programmable controller. The programmablecontroller controls the level of cooling according to instructionsreceived from the digital processing unit based on caloric intake,physical activity, and the desired weight loss regimen. The programmablecontroller of the device is incorporated into a refrigeration unit usedto control the cooling elements. The device includes sensors thatmonitor the caloric intake and physical activity of the subject. Thesensors are associated with a wrist watch-like accessory worn by thesubject during waking hours. Data collected by the wrist watch-likeaccessory are wirelessly transmitted to the digital processing unitprogrammable controller at the end of the waking day. The digitalprocessing unit processes the data into at least one resultinginstruction and provides the at least one resulting instruction to theprogrammable controller See, e.g., FIG. 1.

The device includes a pillow that comes in direct contact with thefacial skin of a subject. An array of flexible rubber tubing forcirculating a cooling fluid is incorporated into one surface of thepillow. The cooling fluid, e.g., water, circulates in a closed circuitthrough the array of tubing in the pillow and into and out of a separaterefrigeration unit. The refrigeration unit is positioned proximal to thesleeping surface and is a small, commercially available, portablerefrigerator/freezer unit (from, e.g., Engel USA, Jupiter, Fla.). Therefrigeration unit is powered using a standard electrical plug or, whena plug is not available, using a rechargeable battery. The cooling wateris pumped from the refrigeration unit through input tubing to spread outinto an array of smaller diameter tubing on the pillow surface. Thecooling water is recollected into output tubing and re-circulated backinto the refrigeration unit for re-cooling.

The temperature and flow rate of the fluid are controlled by aprogrammable controller integrated into the refrigeration unit. Adigital processing unit operably connected to the programmablecontroller and associated with the refrigeration unit can estimate theamount of cooling needed to facilitate weight loss based on datareceived regarding measurements of caloric intake and input fromphysical activity sensors and temperature sensors. The estimate of theamount of cooling needed to facilitate weight loss is dependent upon thecaloric intake and physical activity level of the subject, the amount ofthermogenesis generated by cooling the facial skin, and the desired rateof weight loss, e.g., 1 to 2 pounds per week. In general, weight loss isexpected to occur when the energy expenditure, e.g., activity level andthermogenesis, exceeds the energy consumed, e.g., caloric intake.

The device includes a digital processing unit operably connected to aprogrammable controller. The digital processing unit is configured toreceive information from sensor and process the information into atleast one resulting instruction and provide the at least one resultinginstruction to the programmable controller. The digital processing unitmay be programmable and may include memory and software. The digitalprocessing unit includes at least one processor, such as amicroprocessor or digital signal processor, and an applications programfor calculating energy expenditure and energy consumption by thesubject. The data processing unit may further calculate an effect of thephysiological condition of the subject on the energy expenditure andenergy consumption by the subject.

The digital processing unit receives data from a wrist watch-likeaccessory that collects data regarding caloric intake and physicalactivity of the subject during waking hours. The digital processing unitcan also receive data from an outside operating source, for example acomputing device, such as a personal computing device, smart phone, orpersonal digital assistant. The wrist watch-like accessory has a userinterface for input of caloric intake. See, e.g., U.S. Pat. No.6,675,041, which is incorporated herein by reference. The wristwatch-like accessory can include access to a database having informationregarding one or more analyte levels of normal subjects compared tosubjects having a disease or disorder. The wrist watch-like accessorycan include or interface with a nonphysiologic sensor, for example, anelectronic food detector that can determine mass, volume, or weight offoodstuff to be eaten by the subject and can measure and quantitatecaloric content and nutritional content of foodstuff that will be eatenby the subject. Data from the electronic food detector can becommunicated to the digital processing unit or the programmablecontroller. See, e.g., U.S. Patent Application 2010/0125420;2010/0125419; U.S. 2010/0125418; U.S. 2010/0125417; each of which isincorporated herein by reference. The subject manually enters the typeand estimated quantity of food consumed during the course of wakinghours. The wrist watch-like accessory also collects data from physicalactivity sensors that sense the activity of the subject as measured bysensing heart rate, body temperature, skin resistance,motion/acceleration, and velocity of the subject. See, e.g., U.S. Pat.No. 4,312,358, which is incorporated herein by reference. The data fromthe physical activity sensors are transmitted to the digital processingunit which then processes the data to estimate the physical activitylevel of the subject as reported in calories burned. Data collected bythe wrist watch-like accessory regarding food consumed and physicalactivity during the day are transmitted wirelessly to the digitalprocessing unit at the end of the waking day prior to the subjectfalling asleep on the pillow that includes the cooling device. Thedigital processing unit includes a database of calorie counts forvarious foods and uses the input data from the wrist watch-likeaccessory to calculate the daily caloric intake. The digital processingunit processes the information and provides an instruction to theprogrammable controller, which then adjusts the cooling element todeliver the necessary cooling to the subject.

In some cases, the digital processing unit is also in wirelesscommunication with thermosensors implanted under the skin and in closeproximity to brown adipose depots in the supraclavicular region of thesubject. The thermosensors can monitor the heat generated in the brownadipose tissue depots in response to facial skin cooling. Telemetricsensors for measuring body temperatures are available in various sizesfrom Data Sciences International (St. Paul, Minn.). The digitalprocessing unit uses the data regarding caloric intake, calories burned,and heat generated in the brown adipose depot to estimate energyconsumption. The programmable controller provides instructions to therefrigeration unit to increase or decrease the temperature and/or rateof flow of the water circulating through the pillow to appropriatelymodulate non-shivering thermogenesis in the brown adipose tissue thatresults in an increase or decrease energy consumption and facilitatesweight loss in the subject.

Weight loss in the subject is monitored on a daily to weekly basis usinga standard bathroom scale. The amount of weight lost is manually enteredinto the wrist watch-like accessory. Alternatively, the bathroom scalecan be fitted with a wireless transmitter that automatically transmitsinformation regarding weight to the wrist watch-like accessory, which inturn can be downloaded into the digital processing unit. Based on therate of weight loss over the course of days and/or weeks as well as thedaily caloric intake and physical activity data, the digital processingunit instructs the programmable controller to adjust the temperature andthe flow rate of the cooling fluid circulating through the pillow. Oncethe desired weight has been reached, the device is programmed to providea level of cooling designed to maintain the current desired weight.

Example 4 Device for Treating Diabetes in a Human Subject IncludingInternal Cooling Elements Contacting Visceral Tissue

A device is described that includes cooling elements operating under aprogrammable controller for cooling an area of the body of a humansubject to modulate an activity of brown adipose tissue and thereby totreat a disorder, e.g. metabolic disorder such as diabetes in the humansubject. The device includes multiple internal cooling elements that areapplied to thermoresponsive tissue in an internal abdominal area tomodulate an activity of a brown adipose tissue of the human subject, forexample, to induce non-shivering thermogenesis in the brown adiposetissue of the subject. The cooling elements are anchored to the omentumand in contact with visceral tissues including visceral organs. Thecooling elements have a temperature range from approximately 4° C. toapproximately 37° C. to achieve a visceral tissue temperature rangingapproximately 24° C. to approximately 35° C. to induce non-shiveringthermogenesis in brown adipose tissue of the subject. The multiplecooling elements anchored to the omentum and in contact with visceraltissues can achieve an intra-abdominal regional hypothermia ranging frommild (32-36° C.) to moderate (24-32° C.) temperatures. The devicefurther includes a programmable controller for adaptive programmingdependent upon the level of glucose sensed in the blood of the subject.The device further includes a digital processing unit operatively linkedto the programmable controller. The device further includes a bloodglucose sensor operatively linked to the programmable controller throughthe digital processing unit to sense the levels of glucose in thesubject. The digital processing unit can also receive data regardingfood consumed and can determine an estimate of calories ingested atspecific times of the day and/or during the course of the day. Thedigital processing unit can provide programming to the programmablecontroller. Typically, the level of glucose measured in the blood willfluctuate depending upon when the measurement is taken relative to whenthe last meal was eaten. See, e.g., FIG. 2.

The device includes multiple internal cooling elements anchored to theomentum and in contact with and cooling visceral tissues to achieve anintra-abdominal regional hypothermia. The elements includes a sterile,biocompatible indwelling tube filled with a circulating fluid, e.g.,water, and connected in a closed circuit system to a refrigeration unit.The indwelling tube is surgically implanted into the abdomen, anchoredonto the internal omentum and in contact with the visceral tissues. Theportion of the indwelling tube in direct contact with the visceraltissues is designed to provide increased surface contact with thetissues, either by fanning out into a series of smaller diameter tubes,e.g., capillaries, or by spreading out into a flattened portion of thetube. The surgically implanted indwelling tube includes a port attachedto the skin through which inlet and outlet tubes protrude from the skinand are accessible for attachment to the refrigeration unit to completethe closed circuit cooling system. An example of a port attached to theskin and designed for transcutaneous insertion of a tube is described inNyman, et al., J. Vasc. Interventional Biol., 20: 500-505, 2009, whichis incorporated herein by reference. The device is designed to beambulatory and includes a Peltier-driven portable refrigeration unitincorporated into a backpack or fanny pack. See, e.g., U.S. PatentApplication 2009/0139248, which is incorporated herein by reference. Theportable backpack refrigeration unit is powered by conversion ofmechanical energy generated by the motion of the subject to electricalenergy, using an electricity-generating backpack. See, e.g., U.S. PatentApplication 2009/0015022, which is incorporated herein by reference.

The device includes a programmable controller that controls thetemperature and flow of the fluid circulating into and out of theindwelling tube. The programmable controller is integrated into theportable refrigeration unit and includes a user interface. The userinterface includes a monitor and keypad for use in entering andreceiving instructions, programming or other information.

The device includes a digital processing unit operably linked to theprogrammable controller and configured to receive information from asensor, a timekeeping device, a user interface, or an outside operatingsource and process the information and using the processed informationprovide instruction to the programmable controller.

The digital processing unit is operationally linked to a sensor that canmeasure glucose in the blood of the subject. Glucose is measured using astandard glucose monitor, e.g., GlucoMON®2 wireless glucose meter (fromDiabetech LP, Dallas, Tex.), which can wirelessly send data regardingthe blood glucose levels to the digital processing unit. The subject canalso manually input via a user interface information regarding the foodtypes and estimated quantity consumed during the day. These data areused by the digital processing unit to estimate the subject's caloricintake. The digital processing unit uses the data regarding the bloodglucose levels and the caloric intake to program the programmablecontroller to control the temperature and flow of the circulating waterto induce non-shivering thermogenesis in brown adipose tissue of thesubject. An increase in non-shivering thermogenesis leads to increasedintake of glucose into the brown adipocytes for glucose metabolism, andremoval of glucose from circulation of the subject.

The device operating under a programmable controller for cooling one ormore tissues may control glucose levels in the subject using the glucosemonitor as described above. The degree of cooling by the cooling elementis modulated by the programmable controller accordingly in response tothe glucose monitor and instructions from the digital processing unit.In addition, the intake of glucose into metabolically active brownadipose tissue can be confirmed at certain time points, for examplemonthly, during a programmed cooling period, using the radioactivetracer ¹⁸F-fluorodeoxyglucose and positron emission tomography (PET)combined with computed tomography (CT) scanning. For analysis, thesubject is injected with a bolus of ¹⁸F-fluorodeoxyglucose and subjectedto PET-CT scanning. Cold-induced glucose uptake is monitored in brownadipose tissue of the supraclavicular tissue of the subject and observedas bright sections in the PET-CT scan. The larger the area of brightsections in the scan field, the greater the uptake of¹⁸F-fluorodeoxyglucose into the tissue. See, e.g., Virtanen, et al., N.Engl. J. Med., 360: 1518-1525, 2009, which is incorporated herein byreference.

The use of additional medicaments in the treatment regimen is includedin combination with application of the device described herein tofurther manage the levels of glucose in a human subject with diabetes.The health care provider can prescribe a twice daily injection of aglucagon-like peptide 1 (GLP-1) agonist, e.g., exenatide (Byetta®,Amylin Pharmaceuticals; San Diego, Calif./Eli Lilly; Indianapolis,Ind.), to further manage blood glucose levels in the subject. Exenatideslows adsorption of glucose from the gut, increases insulin secretionfrom the pancreas, lowers high levels of glucagon observed in subjectswith diabetes after meals, and suppresses appetite. An alternative oradditional treatment medicament includes oral treatment withrosiglitazone (Avandia®, GlaxoSmithKline), an insulin sensitizer thatworks by binding to the peroxisome proliferator-activated receptor(PPAR) in adipocytes and making the cells more responsive to insulin.

Example 5 Device for Treating Diabetes in a Human Subject IncludingInternal Cooling Elements Contacting Hypothalamus

A device is described that includes cooling elements operating under aprogrammable controller for cooling an area of the body of a humansubject to stimulate activity and/or proliferation of brown adiposetissue to treat a metabolic disorder, e.g., diabetes, in the humansubject. The device includes an implantable cooling element placed intothe pre-optic area (POA) of the hypothalamus to induce non-shiveringthermogenesis in brown adipose tissue of the subject. Direct cooling ofthe local environment of the POA evokes activation and thermogenesis inbrown adipose tissue. See, e.g., Morrison, et al., Exp. Physiol., 93:773-797, 2008. The cooling element includes a Peltier element tocontrollably cool the hypothalamus. The Peltier element can achievetemperatures ranging from approximately 0° C. to approximately 37° C. toachieve a hypothalamus tissue temperature ranging from approximately 24°C. to approximately 36° C. to induce non-shivering thermogenesis inbrown adipose tissue of the subject. The device further includes aprogrammable controller configured for adaptive programming. Theprogrammable controller is incorporated into a wrist watch-likeaccessory worn by the subject and provides wireless control of thePeltier cooling element. The device further includes a digitalprocessing unit operably linked to the programmable controller. Thedigital processing unit is also in communication with a glucose sensorfor measuring the level of glucose in the blood of the subject. Thedevice further includes an interface for manual or automatic input ofinformation regarding the caloric intake at a certain time of day. Thedigital processing unit processes the data regarding current glucoselevels and caloric intake in the subject and instructs the programmablecontroller to adjust the function of the cooling elements and toregulate the level of non-shivering thermogenesis in brown adiposetissue to provide control of blood glucose levels in the diabeticsubject. See, e.g., FIG. 3.

The device includes an implantable cooling element for implantation intothe hypothalamus of the subject. The implantable cooling elementincludes a Peltier element, a fine thermocouple probe, and a heat sinkas described by Fujioka, et al., Neurosci. Res. 66: 402-405, 2010, whichis incorporated herein by reference. A chip-sized Peltier elementmeasuring approximately 6 mm by 6 mm (from, e.g., Ferrotec, Bedford,N.H.) is combined with a fine thermocouple probe (from, e.g., PhysitempInstruments, Inc., Clifton, N.J.) and a copper heat sink. This portionof the cooling element is covered with a fine layer of medical siliconeor other biocompatible membrane. This portion of the cooling element isimplanted into the hypothalamus using defined stereotactic parametersand a CT scan to assess proper positioning. See, e.g., Schoenen, et al.,Brain, 128: 940-947, which is incorporated herein by reference. Thecopper heat sink is positioned on the heat dissipating side of thePeltier element and the heat from the heat sink is transferred to acirculating fluid that is part of a microchannel cooling system flowingbetween the implanted portion of the cooling element and a locationadjacent to an exterior surface of the subject at the nape of the neck,e.g., adjacent to an epidermal surface or subcutaneous surface. Internalheat transferred from the Peltier element into the circulating fluid istransferred to the external ambient environment through a series oftubes associated with the microchannel cooling system. The thermocoupleis used to measure the temperature of the hypothalamus tissue as it isbeing cooled and can be included in a closed loop system to modulate theactivity of the Peltier element to maintain a desired tissuetemperature. See, e.g., Osorio et al., Medicon 2007, IFMBE Proceedings16: 911-914, 2007, which is incorporated herein by reference.

The programmable controller and digital processing unit of the deviceare located exterior to the subject and are incorporated into adedicated-use handheld unit. The digital processing unit receives andprocesses information regarding physiological conditions from thesensors, determines whether additional cooling is required and instructsthe programmable controller. The digital processing unit and/orprogrammable controller function in the absence of user input, but mayalso include a user interface allowing for input and receipt of data,programming, or other information. The user interface includes a key padas well as a display screen for entering data. The digital processingunit receives information from the glucose sensor via wireless radiofrequency and may employ bluetooth technology. The programmablecontroller communicates with the Peltier element via wireless radiofrequency.

The digital processing unit is in communication with an implantableglucose sensor capable of sensing the subject's blood glucose levels.The subject is equipped with a biocompatible glucose sensor chipimplanted into the abdomen or back of the upper arm of the subject, suchas the sensor forming part of the Freestyle Navigator® glucose monitor.See, e.g., Abbot Diabetes Care, Alameda, Calif. The Freestyle Navigator®glucose monitor is capable of taking glucose measurements on acontinuous basis, e.g., once every minute, and can communicate with anexternal receiver. The external receiver is included in the digitalprocessing unit. The digitized output data stream from the sensor isstored and processed by the digital processing unit.

The human subject uses a food diary incorporated into the handheld unitto enter data regarding the type and quantity of food consumed duringthe course of the day. The handheld unit includes memory for storing adatabase containing information regarding calories and carbohydratecontent of various foods, and the digital processing unit includes acomputational algorithm designed to estimate caloric intake as well ascarbohydrate intake based on these input data. Postprandial bloodglucose levels reflect the amount of carbohydrates consumed by thesubject. This information is processed by the digital processing unit,which provides instructions and programming to the programmablecontroller for adjusting the cooling function of the device includingthe Peltier element. The programmable controller adjusts the amount ofcooling delivered to the hypothalamus as instructed by the digitalprocessing unit based on the blood glucose levels and the caloric intakeand content. Additional medicaments can also be included in thetreatment regimen including medicaments specific for treating Type 1 andType 2, e.g., insulin, a secretagogue, an insulin sensitizer,thiazolidinedione, an α-glucosidase inhibitor, a glucagon-like peptideanalog, a dipeptidyl peptidase-4 inhibitor, an amylin analogue, orcombinations thereof.

Example 6 Device for Treating Obesity in a Human Subject, IncludingInternal Cooling Elements Utilizing an Endothermal Chemical CompositionContacting Colon Tissue

A device is described that includes cooling elements operating under aprogrammable controller for cooling an area of the body of a humansubject to modulate an activity of brown adipose tissue and therebytreat a metabolic disorder, e.g., obesity, in the human subject. Thedevice includes a cooling element that uses an endothermal chemicalcomposition. The portion of the device that includes the cooling elementis inserted into the colon to facilitate cooling of thermoresponsivetissue within the colon. The cooling elements are designed to present atemperature range from approximately 4° C. to approximately 37° C. toachieve a colon tissue temperature ranging from approximately 24° C. toapproximately 32° C. to induce non-shivering thermogenesis in brownadipose tissue of the subject. The device further includes an external,wrist-mounted programmable controller configured for adaptiveprogramming. The wrist-mounted programmable controller includes adigital processing unit and a glucose sensor, as well as a monitor forcaloric intake and caloric expenditure during the course of the day. Thewrist-mounted programmable controller is in wireless communication withthe cooling element inserted into the colon. See, e.g., FIG. 4.

The device includes an implantable portion configured for placement intothe colon, with a cooling element containing an endothermal chemicalcomposition. The implantable portion of the device resembles aself-expanding stent for insertion into the lower colon. See, e.g., U.S.Pat. Nos. 5,876,445; 7,105,175; U.S. Patent Applications 2009/0081271,each of which is incorporated herein by reference. The implantableportion of the device includes two sets of micro-reservoirs, eachcontaining a distinct endothermic chemical, citric acid or sodiumbicarbonate, which upon mixing draws heat from the surroundingenvironment resulting in cooling. The micro-reservoirs are incorporatedinto the wall of the stent-like structure. Examples of implantablestents with at least two reservoirs are described in U.S. PatentApplications 2009/0319026 and 2009/0149947, which is incorporated hereinby reference. Each micro-reservoir containing either citric acid orsodium bicarbonate is covered with a gold foil that, in the presence ofa triggering event such as a voltage, dissolves and releases thecontents of the micro-reservoir. See, e.g., Grayson, et al., Proc. IEEE,92: 6-21, 2004, which is incorporated herein by reference. Citric acidand sodium bicarbonate released from the micro-reservoirs mix in acommon chamber creating an endothermic reaction. The common chamber isin direct contact with the luminal surface of the colon allowing forlocalized cooling. The common chamber also includes a semi-permeablediffusion membrane through which the byproducts of the endothermicreaction can diffuse out of the chamber and into the lumen of the colon.Application of voltage to the microreservoirs containing the endothermalchemical composition is triggered wirelessly by the wrist-mountedprogrammable controller.

The implantable portion of the device including micro-reservoirscontaining an endothermal chemical composition is inserted into thecolon using standard methods for colonic stenting. See, e.g., Piccinni,et al., World J. Gastroenterol., 10: 758-764, 2004, which isincorporated herein by reference. The subject undergoes one or morecolonic enemas to cleanse the colon prior to placement of the device.The subject is placed in a supine position and is administered one ormore sedatives and/or analgesics commonly used for colonoscopy. Thestent-like implantable portion of the device is deployed along a guidewire using fluoroscopic and endoscopic guidance. Endoscopic and/or x-rayimages are used to assess proper placement of the implantable portion ofthe device.

The device further includes a wrist-mounted programmable controller thatcan send wireless instructions to the portion of the device implanted inthe colon. The wrist-mounted programmable controller includes a userinterface with a keypad and LCD screen for inputting and receiving data.The wrist-mounted programmable controller includes a digital programmingunit operationally linked to and capable of receiving information fromsensors that can detect glucose and fatty acids in the blood of thesubject. The glucose and fatty acid sensors are incorporated into theunderside of the wrist-mounted programmable controller and are in directcontact with the skin of the subject. A number of examples ofwrist-mounted sensors for sensing analytes in the blood, includingglucose and fatty acids, have been described. See, e.g., U.S. Pat. Nos.4,953,552; 5,551,953; 5,752,512; 6,151,517, each of which isincorporated herein by reference.

The user interface of the wrist-mounted programmable controller canreceive input data regarding type and quantity of food consumed by thesubject during the course of the day. The data entered by the subjectinto the food diary is used to estimate the caloric intake. Thewrist-mounted programmable controller also includes activity sensors,operationally linked to the digital processing unit, for sensing theactivity of the subject. Such sensors sense heart rate, bodytemperature, skin resistance, motion/acceleration, and velocity. See,e.g., U.S. Pat. No. 4,312,358, which is incorporated herein byreference. Data from the sensors are processed by the digital processingunit to estimate the calories burned during the course of the day. Thedigital processing unit of the wrist-mounted programmable controllerprocesses the data regarding the blood glucose and fatty acid levels,caloric intake, and estimated caloric expenditure and based on theoutcome provides one or more instructions for the programmablecontroller to wirelessly control the release of the endothermicchemicals from the micro-reservoirs in the implantable portion of thedevice to control cooling of the thermoresponsive tissue of the subject.

The subject's weight is monitored on a daily basis using a standardbathroom scale. The amount of weight lost is manually entered into thewrist-mounted programmable controller. Alternatively, the bathroom scalecan be fitted with a wireless transmitter that automatically transmitsinformation regarding weight to the wrist-mounted programmablecontroller. By processing the data acquired regarding the rate of weightloss over the course of days and/or weeks as well as the daily caloricintake and physical activity data, the digital processing unit providesinstruction to the wrist-mounted programmable controller, which adjuststhe frequency of the release of the two endothermic chemicals in theimplantable portion of the device.

The medicament rosiglitazone (Avandia®, GlaxoSmithKline, Inc.) isincluded in the treatment regimen to the augment brown adipose tissuemediated non-shivering thermogenesis treatment. The medicamentrosiglitazone has been shown to increase the expression of uncouplingprotein 1 (UCP-1) in brown adipocytes. See, e.g., Teruel, et al., J.Biol. Chem., 278: 263-269, 2003, which is incorporated herein byreference. Rosiglitazone is dosed orally once or twice daily with atotal daily dose ranging from 4 to 8 mg.

To further augment the brown adipose tissue-mediated non-shiveringthermogenesis, an infusion pump containing norepinephrine, an activatorof brown adipocyte activity, is implanted into or in close proximity tothe brown adipose tissue depots in the supraclavicular region of thesubject. The infusion pump can periodically release minute, localizedamounts of norepinephrine to stimulate the activity of the brownadipocytes. An example of an implantable infusion pump is theSynchroMed® II Pump (from Medtronic, Minneapolis, Minn.). The use of aninfusion pump for administering norepinephrine/noradrenaline to asubject is described in Nagasaka, J. Appl. Physiol., 32: 199-202, 1972,which is incorporated herein by reference.

The use of additional medicaments is included in the treatment regimenin combination with the device described herein to further manage weightloss in an obese subject. The subject can choose to include anover-the-counter weight loss pill, e.g., orlistat (Alli®,GlaxoSmithKline, Inc.), in his or her treatment regimen.

Example 7 Device Including Passive Cooling Elements Contacting a GreatVein for Treating Metabolic Syndrome in a Human Subject

A device is described that includes cooling elements operating under aprogrammable controller for cooling an area of the body of a humansubject to modulate an activity of brown adipose tissue and therebytreat a metabolic disorder, e.g., metabolic syndrome, in the humansubject. The device acts by lowering circulating glucose levels andstimulating weight loss through induction of non-shivering thermogenesisin brown adipose tissue of the subject. The device includes a coolingelement to apply a cooling temperature to thermoresponsive tissue in agreat vein, e.g., the pulmonary vein, of the subject. The coolingelement is a passive cooling system that can controllably cool pulmonaryvein thermoreceptors with little or no energy input. The passive coolingsystem is implanted into the subject and includes a deep portion and ashallow portion. The deep portion of the passive cooling system is inclose proximity to or in direct contact with the pulmonary vein. Theshallow portion of the passive cooling system is implanted just belowthe surface of the subject's skin and participates in passive heattransfer with the ambient environment. The passive cooling system canachieve temperatures ranging from approximately 0° C. to approximately37° C. to achieve a pulmonary vein temperature of approximately 32° C.to induce non-shivering thermogenesis in the subject. The device furtherincludes a programmable controller incorporated into the arm rest of asubject's wheel chair and configured for adaptive programming. Theprogrammable controller includes a digital processing unit incommunication with sensors that can measure physiological indicatorsspecific to metabolic syndrome including levels of glucose andcholesterol, and blood pressure. See, e.g., FIG. 5.

The device described herein includes a passive cooling system includinga deep portion and a shallow portion able to cool pulmonary veinthermoreceptors to induce non-shivering thermogenesis in brown adiposetissue of the subject with minimal energy input to the device. Thepassive cooling system includes a series of tubes and a low-energy pumpthat can circulate a fluid, e.g., water in a closed loop through thedeep and shallow portions of the system. The deep portion of the passivecooling system is implanted in close proximity to or in direct contactwith the pulmonary vein. The shallow portion of the passive coolingsystem is implanted just below the surface of the skin where thetemperature of the subject is closer to ambient temperature, and heatexchange with the external environment is possible. The shallow portionof the passive cooling system is configured in a tentacle-likestructure, allowing the fluid to be spread out over a larger surfacearea to encourage more rapid cooling or equilibrium with the outsideenvironment. The internal body temperature at the site of the deepportion of the passive cooling system is approximately 37° C., whereasthe skin temperature is approximately 32° C. or cooler depending uponthe ambient temperature. The fluid in the passive cooling system ispumped from the relatively cooler environment of the shallow portion tothe relatively warmer environment of the deep portion of the device. Thecooling capacity of the shallow portion of the passive cooling devicecan be increased by application of cold packs to the surface of the skinoverlaying the shallow portion of the implanted passive cooling system.The pump for circulating the fluid through the implanted passive coolingsystem is powered by a body heat energy generator incorporated into theimplanted portion of the device. See, e.g., U.S. Pat. No. 6,075,199,which is incorporated herein by reference.

The device further includes an external programmable controller mountedinto the armrest of the subject's wheelchair and configured to sendwireless instructions to the implanted passive cooling system. Thearmrest-mounted programmable controller includes a user interface with akeypad and LCD screen for inputting data, programming instructions, andother information. The digital processing unit of the armrest-mountedprogrammable controller can receive data regarding the subject's bloodlevels of glucose, fatty acids, and cholesterol, all indicators ofmetabolic syndrome. Blood glucose levels are measured using animplantable glucose sensor such as described in U.S. Pat. No. 7,577,470,which is incorporated herein by reference. The implanted glucose sensoris in wireless communication with the armrest-mounted programmablecontroller. The blood levels of fatty acids and cholesterol are measuredusing standard clinical assays as part of a medical visit, and the datais either entered manually or via wireless communication from an outsidecomputing device into the armrest-mounted programmable controller. Bloodpressure is measured using a form of wrist-mounted blood pressuremonitor associated with the armrest of the wheelchair. Commercialexamples of wrist mounted blood pressure measuring devices have beendescribed. See, e.g., Vasotrac® Blood Pressure Monitor, from Medwave,Arden Hills, Minn.; Omron® Wrist Blood Pressure Monitor, from OmronGlobal, Schaumburg, Ill.

The armrest-mounted programmable controller and its digital processingunit further include the capability of collecting data regarding caloricintake and caloric expenditure. Caloric intake is estimated from thetype and quantity of food ingested by the subject during the course ofthe day. Data regarding the type and quantity of food is manuallyentered into the armrest-mounted programmable controller or iscommunicated wirelessly from an outside computing device and/or outsidesensing device. The outside sensing device can include a nonphysiologicsensor, for example, an electronic food detector that can determinemass, volume, or weight of foodstuff to be eaten by the subject and canmeasure and quantitate caloric content and nutritional content offoodstuff that will be eaten by the subject. Data or other informationfrom the electronic food detector can be communicated to the digitalprocessing unit or the programmable controller. See, e.g., U.S. PatentApplication 2010/0125420; 2010/0125419; U.S. 2010/0125418; U.S.2010/0125417; each of which is incorporated herein by reference. If awheel upholstery-bound subject experiences little or no physicalactivity, the caloric expenditure over a 24 hour period may closelymatch the resting metabolic rate of the subject. The resting metabolicrate of the subject is estimated based on parameters of gender, height,weight, age, temperature, muscular activity, ventilation capacity,caloric intake, drugs, hormones and emotional state entered into theprogrammable controller using the user interface. See, e.g., Lyznicki,et al., Am. Fam. Physician, 63: 2185-2196, 2001, which is incorporatedherein by reference.

By definition, a subject with metabolic syndrome is overweight,especially in and around the abdomen, and exhibits multiple traits thatcan include elevated glucose levels, insulin resistance, elevated serumtriglycerides, decreased HDL cholesterol, and elevated blood pressure.The digital processing unit processes data from periodic monitoring ofthese physiological conditions and their indicators, including andcomparing the data to baseline values and to values from normalindividuals, and provides instruction to the armrest-mountedprogrammable controller. The armrest-mounted programmable controllerwirelessly modulates the action of the pump associated with theimplanted passive cooling system to control the temperature of the fluidreaching the deep portion of the system. The action of the pump isadjusted in response to wireless instructions from the armrest-mountedprogrammable controller. Delivery of more or less cooling to thepulmonary vein thermoreceptors modulates the metabolic activity of thebrown adipose tissue, resulting in increased or decreased levels ofnon-shivering thermogenesis; net increases in non-shiveringthermogenesis serve to lower glucose levels and stimulate weight loss inthe subject. In the long term, continued exposure to cold increases themass of the brown adipose tissue. Increases in mass of the brown adiposetissue in response to long term cooling are monitored using¹⁸F-fluorodeoxyglucose metabolic labeling and PET-CT scanning. See,e.g., Klingenspor, Exp. Physiol. 88: 141-148, 2003; van MarkenLichtenbelt, et al., N. Eng., J. Med., 360: 1500-1508, 2009, each ofwhich is incorporated herein by reference.

Additional medicaments are optionally included in the subject'streatment regimen and can include medicaments specifically designed totreat one or more conditions associated with metabolic syndrome, e.g.,one or more of insulin, secretagogue, insulin sensitizer,thiazolidinedione, α-glucosidase inhibitor, glucagon-like peptideanalog, dipeptidyl peptidase-4 inhibitor, amylin analogue, orcombinations thereof to treat high cholesterol, e.g., one or more of astatin, cholesterol absorption inhibitor, bile acid sequestrant,fibrates, niacin, or combinations thereof to treat high blood pressure,e.g., one or more of a diuretic, beta blocker, ACE inhibitor,angiotensin II receptor blocker, calcium channel blocker, alpha blocker,vasodilator, or combinations thereof. The combination of medicamentsprescribed by the subject's health care provider is dependent upon whichaspects of metabolic syndrome are experienced by the subject.

Each recited range includes all combinations and sub-combinations ofranges, as well as specific numerals contained therein.

All publications and patent applications cited in this specification areherein incorporated by reference to the extent not inconsistent with thedescription herein and for all purposes as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference for all purposes.

Those having ordinary skill in the art will recognize that the state ofthe art has progressed to the point where there is little distinctionleft between hardware and software implementations of aspects ofsystems; the use of hardware or software is generally (but not always,in that in certain contexts the choice between hardware and software canbecome significant) a design choice representing cost vs. efficiencytradeoffs. Those having ordinary skill in the art will recognize thatthere are various vehicles by which processes and/or systems and/orother technologies disclosed herein can be effected (e.g., hardware,software, and/or firmware), and that the preferred vehicle will varywith the context in which the processes and/or systems and/or othertechnologies are deployed. For example, if a surgeon determines thatspeed and accuracy are paramount, the surgeon may opt for a mainlyhardware and/or firmware vehicle; alternatively, if flexibility isparamount, the implementer may opt for a mainly software implementation;or, yet again alternatively, the implementer may opt for somecombination of hardware, software, and/or firmware. Hence, there areseveral possible vehicles by which the processes and/or devices and/orother technologies disclosed herein may be effected, none of which isinherently superior to the other in that any vehicle to be utilized is achoice dependent upon the context in which the vehicle will be deployedand the specific concerns (e.g., speed, flexibility, or predictability)of the implementer, any of which may vary. Those having ordinary skillin the art will recognize that optical aspects of implementations willtypically employ optically-oriented hardware, software, and or firmware.

In a general sense the various aspects disclosed herein which can beimplemented, individually and/or collectively, by a wide range ofhardware, software, firmware, or any combination thereof can be viewedas being composed of various types of “electrical circuitry.”Consequently, as used herein “electrical circuitry” includes, but is notlimited to, electrical circuitry having at least one discrete electricalcircuit, electrical circuitry having at least one integrated circuit,electrical circuitry having at least one application specific integratedcircuit, electrical circuitry forming a general purpose computing deviceconfigured by a computer program (e.g., a general purpose computerconfigured by a computer program which at least partially carries outprocesses and/or devices disclosed herein, or a microdigital processingunit configured by a computer program which at least partially carriesout processes and/or devices disclosed herein), electrical circuitryforming a memory device (e.g., forms of random access memory), and/orelectrical circuitry forming a communications device (e.g., a modem,communications switch, or optical-electrical equipment). The subjectmatter disclosed herein may be implemented in an analog or digitalfashion or some combination thereof.

At least a portion of the devices and/or processes described herein canbe integrated into a data processing system. A data processing systemgenerally includes one or more of a system unit housing, a video displaydevice, memory such as volatile or non-volatile memory, processors suchas microprocessors or digital signal processors, computational entitiessuch as operating systems, drivers, graphical user interfaces, andapplications programs, one or more interaction devices (e.g., a touchpad, a touch screen, an antenna, etc.), and/or control systems includingfeedback loops and control motors (e.g., feedback for sensing positionand/or velocity; control motors for moving and/or adjusting componentsand/or quantities). A data processing system may be implementedutilizing suitable commercially available components, such as thosetypically found in data computing/communication and/or networkcomputing/communication systems.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flowcharts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by those within the art that each function and/or operationwithin such block diagrams, flowcharts, or examples can be implemented,individually and/or collectively, by a wide range of hardware, software,firmware, or virtually any combination thereof. In one embodiment,several portions of the subject matter described herein may beimplemented via Application Specific Integrated Circuits (ASICs), FieldProgrammable Gate Arrays (FPGAs), digital signal processors (DSPs), orother integrated formats. However, some aspects of the embodimentsdisclosed herein, in whole or in part, can be equivalently implementedin integrated circuits, as one or more computer programs running on oneor more computers (e.g., as one or more programs running on one or morecomputer systems), as one or more programs running on one or moreprocessors (e.g., as one or more programs running on one or moremicroprocessors), as firmware, or as virtually any combination thereof,and that designing the circuitry and/or writing the code for thesoftware and or firmware would be well within the skill of one of skillin the art in light of this disclosure. In addition, the mechanisms ofthe subject matter described herein are capable of being distributed asa program product in a variety of forms, and that an illustrativeembodiment of the subject matter described herein applies regardless ofthe particular type of signal bearing medium used to actually carry outthe distribution. Examples of a signal bearing medium include, but arenot limited to, the following: a recordable type medium such as a floppydisk, a hard disk drive, a Compact Disc (CD), a Digital Video Disk(DVD), a digital tape, a computer memory, etc.; and a transmission typemedium such as a digital and/or an analog communication medium (e.g., afiber optic cable, a waveguide, a wired communications link, a wirelesscommunication link (e.g., transmitter, receiver, transmission logic,reception logic, etc.), etc.).

The herein described components (e.g., steps), devices, and objects andthe description accompanying them are used as examples for the sake ofconceptual clarity and that various configuration modifications usingthe disclosure provided herein are within the skill of those in the art.Consequently, as used herein, the specific examples set forth and theaccompanying description are intended to be representative of their moregeneral classes. In general, use of any specific example herein is alsointended to be representative of its class, and the non-inclusion ofsuch specific components (e.g., steps), devices, and objects hereinshould not be taken as indicating that limitation is desired.

With respect to the use of substantially any plural or singular termsherein, the reader can translate from the plural to the singular or fromthe singular to the plural as is appropriate to the context orapplication. The various singular/plural permutations are not expresslyset forth herein for sake of clarity.

The herein described subject matter sometimes illustrates differentcomponents contained within, or connected with, different othercomponents. It is to be understood that such depicted architectures aremerely examples, and that in fact many other architectures can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” such that the desired functionality isachieved. Hence, any two components herein combined to achieve aparticular functionality can be seen as “associated with” each othersuch that the desired functionality is achieved, irrespective ofarchitectures or intermedial components. Likewise, any two components soassociated can also be viewed as being “operably connected,” or“operably coupled,” to each other to achieve the desired functionality,and any two components capable of being so associated can also be viewedas being “operably couplable,” to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to physically mateable or physically interacting componentsor wirelessly interactable or wirelessly interacting components orlogically interacting or logically interactable components.

While particular aspects of the present subject matter described hereinhave been shown and described, changes and modifications may be madewithout departing from the subject matter described herein and itsbroader aspects and, therefore, the appended claims are to encompasswithin their scope all such changes and modifications as are within thetrue spirit and scope of the subject matter described herein.Furthermore, it is to be understood that the invention is defined by theappended claims. It will be understood that, in general, terms usedherein, and especially in the appended claims (e.g., bodies of theappended claims) are generally intended as “open” terms (e.g., the term“including” should be interpreted as “including but not limited to,” theterm “having” should be interpreted as “having at least,” the term“includes” should be interpreted as “includes but is not limited to,”etc.). It will be further understood that if a specific number of anintroduced claim recitation is intended, such an intent will beexplicitly recited in the claim, and in the absence of such recitationno such intent is present. For example, as an aid to understanding, thefollowing appended claims may contain usage of the introductory phrases“at least one” and “one or more” to introduce claim recitations.However, the use of such phrases should not be construed to imply thatthe introduction of a claim recitation by the indefinite articles “a” or“an” limits any particular claim containing such introduced claimrecitation to inventions containing only one such recitation, even whenthe same claim includes the introductory phrases “one or more” or “atleast one” and indefinite articles such as “a” or “an”; the same holdstrue for the use of definite articles used to introduce claimrecitations. In addition, even if a specific number of an introducedclaim recitation is explicitly recited, such recitation should typicallybe interpreted to mean at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, typicallymeans at least two recitations, or two or more recitations).Furthermore, in those instances where a convention analogous to “atleast one of A, B, and C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (e.g., “a system having at least one of A, B, and C”would include but not be limited to systems that have A alone, B alone,C alone, A and B together, A and C together, B and C together, or A, B,and C together, etc.). In those instances where a convention analogousto “at least one of A, B, or C, etc.” is used, in general such aconstruction is intended in the sense one having skill in the art wouldunderstand the convention (e.g., “a system having at least one of A, B,or C” would include but not be limited to systems that have A alone, Balone, C alone, A and B together, A and C together, B and C together, orA, B, and C together, etc.). Virtually any disjunctive word and/orphrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

What is claimed is: 1.-144. (canceled)
 145. A system comprising: one ormore cooling elements configured for application to an external surfaceof a subject to modulate at least one activity of brown adipose tissueof the subject; at least one neurostimulator configured to stimulate atleast one nerve of the subject; and a programmable controller operablycoupled to the one or more cooling elements and the at least oneneurostimulator, the programmable controller configured to provideinstructions to the one or more cooling elements and the at least oneneurostimulator in response to information regarding at least one of anumber of calories ingested by the subject or a type and quantity offood ingested by the subject.
 146. The system of claim 145, furthercomprising programming designed to induce weight loss.
 147. The systemof claim 145, further comprising a digital processing unit operablyconnected to the programmable controller, the digital processing unitconfigured to receive information from at least one of a sensor, atimekeeping device, a user interface, and an outside operating source,to process the information into at least one resulting instruction, andto provide the at least one resulting instruction to the programmablecontroller.
 148. The system of claim 145, further comprising an outsideoperating source operably connected to the programmable computer,wherein the outside operating source is configured to transmitinformation to the programmable computer regarding the at least one ofthe number of calories ingested by the subject or the type and thequantity of food ingested by the subject.
 149. The system of claim 148,wherein the outside operating source comprises a smart phone.
 150. Thesystem of claim 148, wherein the outside operating source comprises awearable device.
 151. The system of claim 148, wherein the outsideoperating source comprises an electronic food detector configured todetermine at least one of mass, volume, weight, or caloric content ofthe food ingested by the subject.
 152. The system of claim 145, whereinthe programmable controller is incorporated into a smart phone.
 153. Thesystem of claim 145, wherein the programmable controller is incorporatedinto a wearable device.
 154. The system of claim 145, wherein the one ormore cooling elements are attached to a substrate sized for placement onthe external surface of the subject.
 155. The system of claim 154,wherein at least one surface of the substrate includes an adhesivematerial for attachment of the substrate to the external surface of thesubject.
 156. The system of claim 145, wherein the one or more coolingelements are attached to a substrate sized for placement on the externalsurface of the subject in proximity to thermoresponsive tissue of thesubject, wherein the thermoresponsive tissue includes at least one ofnervous tissue or brown adipose tissue of the subject.
 157. The systemof claim 145, wherein the one or more cooling elements are attached to asubstrate sized for placement on the external surface of the subject inproximity to one or more blood vessels or lymph vessels of the subject.158. The system of claim 145, wherein the one or more cooling elementsand the at least one neurostimulator are attached to a substrate sizedfor placement on the external surface of the subject.
 159. The system ofclaim 145, wherein the one or more cooling elements are sized forincorporation into bedding, furniture, or upholstery and positioned tocome in contact with the external surface of the subject to modulate theat least one activity of the brown adipose tissue of the subject. 160.The system of claim 145, wherein the one or more cooling elements aresized for incorporation into an article of clothing.
 161. The system ofclaim 145, wherein the at least one neurostimulator comprises animplanted neurostimulator.
 162. The system of claim 145, wherein the atleast one neurostimulator comprises a cutaneous neurostimulator
 163. Thesystem of claim 145, wherein the at least one neurostimulator is sizedto stimulate a portion of the vagus nerve to suppress appetite.
 164. Thesystem of claim 145, wherein the at least one neurostimulator is sizedand positioned to stimulate nerves involved in inducing thermogenesis.165. The system of claim 145, wherein the at least one neurostimulatorcomprises at least one of an electric neurostimulator, a magneticneurostimulator, an ultrasound neurostimulator, or a microwaveneurostimulator.
 166. The system of claim 145, wherein the one or morecooling elements and the at least one neurostimulator are contained in asingle packaged unit sized for application to the external surface ofthe subject.
 167. The system of claim 145, wherein the one or morecooling elements are sized to cool a first portion of the subject andthe at least one neurostimulator is sized to stimulate a second portionof the subject.
 168. The system of claim 145, wherein the one or morecooling elements and the at least one neurostimulator are sized torespectively cool and stimulate the same portion of the subject. 169.The system of claim 145, further comprising one or more sensors operablyconnected to the programmable controller, wherein the programmablecontroller is configured to provide instructions to at least one of theone or more cooling elements and the at least one neurostimulator inresponse to information from the one or more sensors, wherein the one ormore sensors are configured to sense one or more physiologicalconditions of the subject.
 170. The system of claim 169, wherein the oneor more sensors comprise one or more analyte sensors configured to sensea plasma level of one or more of a metabolic analyte, a sugar, alipoprotein, or a fatty acid in the subject.
 171. The system of claim169, wherein the one or more sensors comprise one or more temperaturesensors configured to sense a temperature of the subject.
 172. Thesystem of claim 169, wherein the one or more sensors comprise one ormore activity sensors configured to sense a physical activity level ofthe subject.
 173. A system comprising: one or more cooling elementsconfigured for application to an external surface of a subject tomodulate at least one activity of brown adipose tissue of the subject;at least one neurostimulator configured to stimulate at least one nerveof the subject; at least one physiological sensor incorporated into awearable device; and a programmable controller operably coupled to theone or more cooling elements, the at least one neurostimulator, and theat least one physiological sensor incorporated into the wearable device,the programmable controller configured to receive information from theat least one physiological sensor regarding a physiological condition ofthe subject and to provide instructions to the one or more coolingelements and the at least one neurostimulator in response to informationregarding the physiological condition of the subject.
 174. The system ofclaim 173, wherein the at least one physiological sensor incorporatedinto the wearable device comprises at least one analyte sensorconfigured to sense a plasma level of one or more of a metabolicanalyte, a sugar, a lipoprotein, or a fatty acid of a subject; andwherein the programmable controller is configured to receive informationfrom the at least one analyte sensor regarding the plasma level of theone or more of the metabolic analyte, the sugar, the lipoprotein, or thefatty acid in the subject and to provide instructions to the one or morecooling elements and to the at least one neurostimulator in response tothe received information from the at least one analyte sensor.
 175. Thesystem of claim 173, wherein the at least one physiological sensorincorporated into the wearable device comprises at least one temperaturesensor positioned to measure a temperature of the subject; and whereinthe programmable controller is configured to receive information fromthe at least one temperature sensor regarding the measured temperatureof the subject and to provide instructions to the one or more coolingelements and to the at least one neurostimulator in response to thereceived information from the at least one temperature sensor.
 176. Thesystem of claim 173, wherein the at least one physiological sensorincorporated into the wearable device comprises at least one physicalactivity sensor configured to measure a physical activity level of thesubject; and wherein the programmable controller is configured toreceive information from the at least one physical activity sensorregarding the measured physical activity level of the subject and toprovide instructions to the one or more cooling elements and to the atleast one neurostimulator in response to the received information fromthe at least one physical activity sensor.
 177. The system of claim 173,wherein the wearable device comprises a wrist watch-like device. 178.The system of claim 173, wherein the programmable controller isincorporated into the wearable device, and wherein the programmablecontroller is in wireless communication with the one or more coolingelements and the at least one neurostimulator.
 179. The system of claim173, wherein at least one of the one or more cooling elements and the atleast one neurostimulator are attached to a substrate sized forapplication to the external surface of the subject, wherein at least onesurface of the substrate includes an adhesive for attachment of thesubstrate to the external surface of the subject.
 180. The system ofclaim 173, wherein the at least one of the one or more cooling elementsand the at least one neurostimulator are sized for incorporation intobedding, upholstery, or furniture and positioned to come into contactwith the external surface of the subject.
 181. The system of claim 173,wherein the one or more cooling elements and the at least oneneurostimulator are contained in a single packaged unit sized forapplication to the external surface of the subject; wherein theprogrammable controller is incorporated into the wearable deviceincluding the at least one physiological sensor; and wherein theprogrammable controller wirelessly provides the instructions to the atleast one of the one or more cooling elements and the at least oneneurostimulator in response to the information received from the atleast one physiological sensor regarding the physiological condition ofthe subject.